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Journal of Neurochemistry

Current research articles..




The scientific Journal of Neurochemistry continues to be a leading source for research into all aspects of neuroscience, with a particular focus on molecular and cellular aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers.

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Additional research articles see Current Chemistry Research Articles. Magazines with similar content (neurochemistry):

 - Neurochemistry International.



Journal of Neurochemistry - Abstracts



Ndrg2 deficiency ameliorates neurodegeneration in experimental autoimmune encephalomyelitis

N-myc downstream-regulated gene 2 (NDRG2) is a differentiation- and stress-associated molecule that is predominantly expressed in astrocytes in the central nervous system. In this study, we examined the expression and role of NDRG2 in experimental autoimmune encephalomyelitis (EAE), which is an animal model of multiple sclerosis. Western blot and immunohistochemical analysis revealed that the expression of NDRG2 was observed in astrocytes of spinal cord, and was enhanced after EAE induction. A comparative analysis of wild-type and Ndrg2−/− mice revealed that deletion of Ndrg2 ameliorated the clinical symptoms of EAE. Although Ndrg2 deficiency only slightly affected the inflammatory response, based on the results of flow cytometry, qRT-PCR, and immunohistochemistry, it significantly reduced demyelination in the chronic phase, and, more importantly, neurodegeneration both in the acute and chronic phases. Further studies revealed that the expression of astrocytic glutamate transporters, including glutamate aspartate transporter (GLAST) and glutamate transporter 1, was more maintained in the Ndrg2−/− mice compared with wild-type mice after EAE induction. Consistent with these results, studies using cultured astrocytes revealed that Ndrg2 gene silencing increased the expression of GLAST, while NDRG2 over-expression decreased it without altering the expression of glial fibrillary acidic protein. The effect of NDRG2 on GLAST expression was associated with the activation of Akt, but not with the activation of nuclear factor-kappa B. These findings suggest that NDRG2 plays a key role in the pathology of EAE by modulating glutamate metabolism. In this study, we examined the expression and role of an astrocytic protein NDRG2 in experimental autoimmune encephalomyelitis, which is an animal model of multiple sclerosis. We observed that NDRG2 plays pathological roles in EAE most strongly at the step of neurodegeneration. NDRG2 regulates the expression of glutamate transporters through, at least in part, the PI3K/Akt signaling pathway. NDRG2-expressiong astrocytes may be a novel target in MS and in other related diseases.
Datum: 20.02.2018


Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson's disease

Parkinson's disease (PD) is a movement disorder with widespread neurodegeneration in the brain. Significant oxidative, reductive, metabolic, and proteotoxic alterations have been observed in PD postmortem brains. The alterations of mitochondrial function resulting in decreased bioenergetic health is important and needs to be further examined to help develop biomarkers for PD severity and prognosis. It is now becoming clear that multiple hits on metabolic and signaling pathways are likely to exacerbate PD pathogenesis. Indeed, data obtained from genetic and genome association studies have implicated interactive contributions of genes controlling protein quality control and metabolism. For example, loss of key proteins that are responsible for clearance of dysfunctional mitochondria through a process called mitophagy has been found to cause PD, and a significant proportion of genes associated with PD encode proteins involved in the autophagy-lysosomal pathway. In this review, we highlight the evidence for the targeting of mitochondria by proteotoxic, redox and metabolic stress, and the role autophagic surveillance in maintenance of mitochondrial quality. Furthermore, we summarize the role of α-synuclein, leucine-rich repeat kinase 2, and tau in modulating mitochondrial function and autophagy. Among the stressors that can overwhelm the mitochondrial quality control mechanisms, we will discuss 4-hydroxynonenal and nitric oxide. The impact of autophagy is context depend and as such can have both beneficial and detrimental effects. Furthermore, we highlight the potential of targeting mitochondria and autophagic function as an integrated therapeutic strategy and the emerging contribution of the microbiome to PD susceptibility. This review provides highlights on recent observations regarding the multifacet impact of pathological proteins, endogenously produced reactive species, environmental toxins, and metabolism including glucose and fatty acid metabolism, on mitochondria – autophagy function, in the context of Parkinson's disease. The review also discusses future studies of designing targeted strategies to aid the treatment of Parkinson's disease.
Datum: 14.02.2018


Palmitate-induced C/EBP homologous protein activation leads to NF-κB-mediated increase in BACE1 activity and amyloid beta genesis

The etiology of Alzheimer's disease (AD) is egregiously comprehended, but epidemiological studies have posited that diets rich in the saturated fatty acid palmitic acid (palmitate) are a significant risk factor. The production and accumulation of amyloid beta peptide (Aβ) is considered the core pathological molecular event in the pathogenesis of AD. The rate-limiting step in Aβ genesis from amyloid-β precursor protein (AβPP) is catalyzed by the enzyme β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the expression and enzymatic activity of which is significantly up-regulated in the AD brain. In this study, we determined the molecular mechanisms that potentially underlie the palmitate-induced up-regulation in BACE1 expression and augmented Aβ production. We demonstrate that a palmitate-enriched diet and exogenous palmitate treatment evoke an increase in BACE1 expression and activity leading to enhanced Aβ genesis in the mouse brain and SH-SY5Y-APPSwe cells, respectively, through the activation of the transcription factor NF-κB. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays revealed that palmitate enhances BACE1 expression by increasing the binding of NF-κB in the BACE1 promoter followed by an enhancement in the transactivation of the BACE1 promoter. Elucidation and delineation of upstream molecular events unveiled a critical role of the endoplasmic reticulum stress-associated transcription factor, C/EBP homologous protein (CHOP) in the palmitate-induced NF-κB activation, as CHOP knock-down cells and Chop−/− mice do not exhibit the same degree of NF-κB activation in response to the palmitate challenge. Our study delineates a novel CHOP-NF-κB signaling pathway that mediates palmitate-induced up-regulation of BACE1 expression and Aβ genesis. The mechanisms that underlie the palmitate-enriched diet-induced increase in amyloid beta (Aβ) burden in the brain and subsequent increase in the risk of Alzheimer's disease are poorly comprehended. Herein, we show that palmitate-enriched diet causes C/EBP homologous protein (CHOP) activation resulting in an increase in NF-κB transcriptional activity mediated transactivation of the β-site APP cleaving enzyme 1 (BACE1) promoter. The ensuing increase in BACE1 protein levels and BACE1 enzymatic activity results in a significant increase in Aβ genesis and augmentation in the neurodegenerative cascade inherent in Alzheimer's disease.
Datum: 14.02.2018


A dual role for Integrin α6β4 in modulating hereditary neuropathy with liability to pressure palsies

Peripheral myelin protein 22 (PMP22) is a component of compact myelin in the peripheral nervous system. The amount of PMP22 in myelin is tightly regulated, and PMP22 over or under-expression cause Charcot-Marie-Tooth 1A (CMT1A) and Hereditary Neuropathy with Pressure Palsies (HNPP). Despite the importance of PMP22, its function remains largely unknown. It was reported that PMP22 interacts with the β4 subunit of the laminin receptor α6β4 integrin, suggesting that α6β4 integrin and laminins may contribute to the pathogenesis of CMT1A or HNPP. Here we asked if the lack of α6β4 integrin in Schwann cells influences myelin stability in the HNPP mouse model. Our data indicate that PMP22 and β4 integrin may not interact directly in myelinating Schwann cells, however, ablating β4 integrin delays the formation of tomacula, a characteristic feature of HNPP. In contrast, ablation of integrin β4 worsens nerve conduction velocities and non-compact myelin organization in HNPP animals. This study demonstrates that indirect interactions between an extracellular matrix receptor and a myelin protein influence the stability and function of myelinated fibers. Laminin receptor integrin α6β4 modulates peripheral myelin protein 22 (PMP22) neuropathy. In this study, we employed biochemical and genetic studies to shed light on the relationship between PMP22 and signaling from the Schwann cell extracellular matrix. We demonstrate that ablation of β4 integrin delays the progression of Hereditary Neuropathy with Pressure Palsy (HNPP), but also causes a reduction in the speed of action potential propagation in HNPP animals. These findings suggest that in HNPP, integrin α6β4 has opposing effects on two distinct pathomechanisms, i.e. the formation of tomacula and the propagation of action potentials.
Datum: 13.02.2018


Stress-induced tRNA cleavage and tiRNA generation in rat neuronal PC12 cells

Transfer RNA (tRNA) plays a role in stress response programs involved in various pathological conditions including neurological diseases. Under cell stress conditions, intracellular tRNA is cleaved by a specific ribonuclease, angiogenin, generating tRNA-derived fragments or tRNA-derived stress-induced RNA (tiRNA). Generated tiRNA contributes to the cell stress response and has potential cell protective effects. However, tiRNA generation under stress conditions in neuronal cells has not been fully elucidated. To examine angiogenin-mediated tiRNA generation in neuronal cells, we used the rat neuronal cell line, PC12, in combination with analysis of SYBR staining and immuno-northern blotting using anti-1-methyladenosine antibody, which specifically and sensitively detects tiRNA. Oxidative stress induced by arsenite and hydrogen peroxide caused tRNA cleavage and tiRNA generation in PC12 cells. We also demonstrated that oxygen-glucose deprivation, which is an in vitro model of ischemic–reperfusion injury, induced tRNA cleavage and tiRNA generation. In these stress conditions, the amount of generated tiRNA was associated with the degree of morphological cell damage. Time course analysis indicated that generation of tiRNA was prior to severe cell damage and cell death. Angiogenin overexpression did not influence the amount of tiRNA in normal culture conditions; however, it significantly increased tiRNA generation induced by cell stress conditions. Our findings show that angiogenin-mediated tiRNA generation can be induced in neuronal cells by different cell stressors, including ischemia–reperfusion. Additionally, detection of tiRNA could be used as a potential cell damage marker in neuronal cells. This article is protected by copyright. All rights reserved.
Datum: 12.02.2018


Bidirectional variation in glutamate efflux in the medial prefrontal cortex induced by selective positive and negative allosteric mGluR5 modulators

Dysregulation of prefrontal cortical glutamatergic signalling via NMDA receptor hypofunction has been implicated in cognitive dysfunction and impaired inhibitory control in such neuropsychiatric disorders as schizophrenia, attention-deficit hyperactivity disorder and drug addiction. Although NMDA receptors functionally interact with metabotropic glutamate receptor 5 (mGluR5), the consequence of this interaction for glutamate release in the prefrontal cortex (PFC) remains unknown. We therefore investigated the effects of positive and negative allosteric mGluR5 modulation on changes in extracellular glutamate efflux in the medial PFC (mPFC) induced by systemic administration of the non-competitive NMDA receptor antagonist dizocilpine (or MK801) in rats. Extracellular glutamate efflux was measured following systemic administration of the positive allosteric mGluR5 modulator [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone] (ADX47273; 100 mg/kg, p.o.) and negative allosteric mGluR5 modulator [2-chloro-4-{[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-yl]ethynyl}pyridine] (RO4917523; 0.3 mg/kg, p.o.), using a wireless glutamate biosensor in awake, freely moving rats. The effect of MK801 (0.03–0.06 mg/kg, s.c.) on mPFC glutamate efflux was also investigated in addition to the effects of MK801 (0.03 mg/kg, s.c.) following ADX47273 (100 mg/kg, p.o.) pre-treatment. ADX47273 produced a sustained increase in glutamate efflux and increased the effect of NMDA receptor antagonism on glutamate efflux in the mPFC. In contrast, negative allosteric mGluR5 modulation with RO4917523 decreased glutamate efflux in the mPFC. These findings indicate that positive and negative allosteric mGluR5 modulators produce long lasting and opposing actions on extracellular glutamate efflux in the mPFC. Positive and negative allosteric modulators of mGluR5 may therefore be viable therapeutic agents to correct abnormalities in glutamatergic signalling present in a range of neuropsychiatric disorders. NMDA-receptor-dependent abnormal prefrontal glutamatergic signalling is linked to neuropsychiatric disorders. Although NMDA receptors interact with mGluR5, the consequence on glutamate efflux remains unknown. We demonstrate that mGluR5-positive allosteric modulation (PAM) increased prefrontal glutamate efflux and potentiated the effect of NMDA receptor antagonism, whereas negative allosteric modulation (NAM) decreased this measure. These agents may correct glutamatergic abnormalities clinically.
Datum: 12.02.2018


The APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation, Ca2+ dysregulation, and mitochondrial abnormalities

Growing evidence suggests a close relationship between Alzheimer′s Disease (AD) and cerebral hypoxia. Astrocytes play a key role in brain homeostasis and disease states, while some of the earliest changes in AD occur in astrocytes. We have therefore investigated whether mutations associated with AD increase astrocyte vulnerability to ischemia. Two astroglioma cell lines derived from APPSWE/PS1A246E (APP, amyloid precursor protein; PS1, presenilin 1) transgenic mice and controls from normal mice were subjected to oxygen and glucose deprivation (OGD), an in vitro model of ischemia. Cell death was increased in the APPSWE/PS1A246E line compared to the control. Increasing extracellular calcium concentration ([Ca2+]) exacerbated cell death in the mutant but not in the control cells. In order to explore cellular Ca2+ homeostasis, the cells were challenged with ATP or thapsigargin and [Ca2+] was measured by fluorescence microscopy. Changes in cytosolic Ca2+ concentration ([Ca2+]c) were potentiated in the APPSWE/PS1A246E transgenic line. Mitochondrial function was also altered in the APPSWE/PS1A246E astroglioma cells; mitochondrial membrane potential and production of reactive oxygen species were increased, while mitochondrial basal respiratory rate and ATP production were decreased compared to control astroglioma cells. These results suggest that AD mutations in astrocytes make them more sensitive to ischemia; Ca2+ dysregulation and mitochondrial dysfunction may contribute to this increased vulnerability. Our results also highlight the role of astrocyte dyshomeostasis in the pathophysiology of neurodegenerative brain disorders. Growing evidence suggests a close relationship between Alzheimer´s Disease (AD) and cerebral hypoxia. Astrocytes play a key role in brain homeostasis and disease states, while some of the earliest changes in AD occur in astrocytes. We have found that an astroglial cell line carrying two Alzheimer's disease-related mutations (APPSWE/PS1A246E) are more vulnerable to an ischemia model. This might be because of increased Ca2+ signaling, increased ROS generation, and mitochondrial dysfunction. Our results highlight the contribution of astrocytes in the relationship between AD and brain ischemia and the contribution of astrocytes to the pathophysiology of neurodegenerative diseases.
Datum: 12.02.2018


The many faces of vascular cognitive impairment

This Preface introduces the articles of the special issue on “Vascular Dementia” in which several recognized experts provide an overview of this research field. The brain is a highly vascularized organ and consequently, vascular dysfunction and related pathways affect cognitive performance and memory. Vascular dementia or vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease, and both disorders often occur in parallel. With this special issue, we hope to provide insight and a stimulating discussion for the future development of this research field. This article is part of the Special Issue “Vascular Dementia”. This Preface introduces the articles of the special issue on “Vascular Dementia” in which several recognized experts provide an overview of this research field. The brain is a highly vascularized organ and consequently, vascular dysfunction and related pathways affect cognitive performance and memory. Vascular dementia or vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease, and both disorders often occur in parallel. With this special issue, we hope to provide insight and a stimulating discussion for the future development of this research field. This article is part of the Special Issue “Vascular Dementia”.
Datum: 12.02.2018


Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain

One carbon metabolism is regulated by the availability of nutrients known as methyl donors, and disruption of this pathway can affect multiple physiological systems. DNA methylation, critical for the regulation of gene expression, is linked to one carbon metabolism, and can be altered by perinatal diet. In the current study, dams (n=12/group) were fed HF or standard control (SC) diet through pregnancy and lactation, and male and female offspring were then fed either SC or methyl donor supplemented diet (MDS) between 3 and 6 weeks of age (n=20-26/group). Concentration of one carbon intermediates and other related metabolites were assessed within brain tissue (prefrontal cortex, PFC) through the use of mass spectrometry at 6 weeks of age. Additionally, expression of target genes and enzymes that participate in DNA methylation or are relevant to one carbon metabolism were measured. We found that MDS increases the concentration of folate intermediates in the PFC, and that this increase is blunted in male offspring from dams fed a HF diet. Additionally, perinatal HF diet increased the concentration of cysteine in the PFC of both male and female offspring, consistent with oxidative stress. Further, both maternal HF diet and postnatal MDS altered global DNA methylation in the PFC in males but not females. Collectively, these data demonstrate sex differences in changes in one carbon metabolites in the prefrontal cortex in response to early life high fat diet and methyl donor supplementation. This article is protected by copyright. All rights reserved.
Datum: 09.02.2018


Mitochondrial dysfunction in human skeletal muscle biopsies of lipid storage disorder

Mitochondria regulate the balance between lipid metabolism and storage in the skeletal muscle. Altered lipid transport, metabolism and storage influence the bioenergetics, redox status and insulin signalling contributing to cardiac and neurological diseases. Lipid storage disorders (LSDs) are neurological disorders which entail intramuscular lipid accumulation and impaired mitochondrial bioenergetics in the skeletal muscle causing progressive myopathy with muscle weakness. However, the mitochondrial changes including molecular events associated with impaired lipid storage have not been completely understood in the human skeletal muscle. We carried out morphological and biochemical analysis of mitochondrial function in muscle biopsies of human subjects with LSDs (n=7) compared to controls (n=10). Routine histology, enzyme histochemistry and ultrastructural analysis indicated altered muscle cell morphology and mitochondrial structure. Protein profiling of the muscle mitochondria from LSD samples (n=5) (vs. control, n=5) by high throughput mass spectrometric analysis revealed that impaired metabolic processes could contribute to mitochondrial dysfunction and ensuing myopathy in LSDs. We propose that impaired fatty acid and respiratory metabolism along with increased membrane permeability, elevated lipolysis and altered cristae entail mitochondrial dysfunction in LSDs. Some of these mechanisms were unique to LSD apart from others common to dystrophic and inflammatory muscle pathologies. Many differentially regulated mitochondrial proteins in LSD are linked with other human diseases indicating that mitochondrial protection via targeted drugs could be a treatment modality in LSD and related metabolic diseases. This article is protected by copyright. All rights reserved.
Datum: 09.02.2018


Early CALP2 expression and microglial activation are potential inducers of spinal IL-6 upregulation and bilateral pain following motor nerve injury

Previous work from our laboratory showed that motor nerve injury by lumbar 5 ventral root transection (L5-VRT) led to interleukin-6 (IL-6) overexpression in bilateral spinal cord, and that intrathecal administration of IL-6 neutralizing antibody delayed the induction of mechanical allodynia in bilateral hind paws. However, early events and upstream mechanisms underlying spinal IL-6 expression following L5-VRT require elucidation. The model of L5-VRT was used to induce neuropathic pain, which was assessed with von Frey hairs and the plantar tester in adult male Sprague-Dawley rats. Calpain-2 (CALP2, a calcium-dependent protease) knockdown or overexpression and microglia depletion were conducted intrathecally. Western blots and immunohistochemistry were performed to explore the possible mechanisms. Here, we provide the first evidence that both IL-6 and CALP2 levels are increased in lumbar spinal cord within 30 min following L5-VRT. IL-6 and CALP2 co-localized in both spinal dorsal horn (SDH) and spinal ventral horn (SVH). Postoperative (PO) increase of CALP2 in ipsilateral SDH was evident at 10 min PO, preceding increased IL-6 at 20 min PO. Knockdown of spinal CALP2 by intrathecal CALP2-shRNA administration prevented VRT-induced IL-6 overproduction in ipsilateral spinal cord and alleviated bilateral mechanical allodynia. Spinal microglia activation also played a role in early IL-6 upregulation. Macrophage/microglia markers ED1/Iba1 were increased at 30 min PO, while GFAP (astrocyte) and CNPase (oligodendrocyte) markers were not. Increased Iba1 was detected as early as 20 min PO and peaked at 3 days. Morphology changed from a small soma with fine processes in resting cells to an activated amoeboid shape. Depletion of microglia using Mac-1-saporin partially prevented IL-6 upregulation and attenuated VRT-induced bilateral mechanical allodynia. Taken together, our findings provide evidence that increased spinal cord CALP2 and microglia cell activation may have early causative roles in IL-6 overexpression following motor nerve injury. Agents that inhibit CALP2 and/or microglia activation may therefore prove valuable for treating neuropathic pain. This article is protected by copyright. All rights reserved.
Datum: 09.02.2018


Alterations in mGlu5 receptor expression and function in the striatum in a rat depression model

Major depressive disorder is a common form of mental illness. Many brain regions are implicated in the pathophysiology and symptomatology of depression. Among key brain areas is the striatum that controls reward and mood and is involved in the development of core depression-like behavior in animal models of depression. While molecular mechanisms in this region underlying depression-related behavior are poorly understood, the glutamatergic input to the striatum is believed to play a role. In this study, we investigated changes in metabotropic glutamate (mGlu) receptor expression and signaling in the striatum of adult rats in response to prolonged (10–12 weeks) social isolation, a pre-validated animal paradigm modeling depression in adulthood. We found that mGlu5 receptor protein levels in the striatum were increased in rats that showed typical depression- and anxiety-like behavior after chronic social isolation. This increase in mGlu5 receptor expression was seen in both subdivisions of the striatum, the nucleus accumbens and caudate putamen. At subcellular and subsynaptic levels, mGlu5 receptor expression was elevated in surface membranes at synaptic sites. In striatal neurons, the mGlu5-associated phosphoinositide signaling pathway was augmented in its efficacy after prolonged social isolation. These data indicate that the mGlu5 receptor is a sensitive substrate of depression. Adulthood social isolation leads to the up-regulation of mGlu5 receptor expression and function in striatal neurons. This study was carried out to monitor changes in group I metabotropic glutamate (mGlu) receptors in the striatum in a rat depression model. Striatal mGlu5 receptor proteins were elevated in adult rats that showed typical depression- and anxiety-like behavior after chronic social isolation. mGlu5 receptors were elevated in surface membranes at synaptic sites. The mGlu5-associated inositol-1,4,5-triphosphate (IP3) signaling was augmented in socially isolated rats. Thus, adulthood social isolation leads to the up-regulation of mGlu5 receptors in striatal neurons.
Datum: 08.02.2018


Intracerebroventricular administration of Cystatin C ameliorates disease in SOD1-linked amyotrophic lateral sclerosis mice

Cystatin C (CysC) is a major protein component of Bunina bodies, which are a pathological hallmark observed in the remaining motor neurons of patients with amyotrophic lateral sclerosis (ALS). Dominant mutations in the SOD1 gene, encoding Cu/Zn superoxide dismutase (SOD1), are causative for a subset of inherited ALS cases. Our previous study showed that CysC exerts a neuroprotective effect against mutant SOD1-mediated toxicity in vitro; however, in vivo evidence of the beneficial effects mediated by CysC remains obscure. Here we examined the therapeutic potential of recombinant human CysC in vivo using a mouse model of ALS in which the ALS-linked mutated SOD1 gene is expressed (SOD1G93A mice). Intracerebroventricular administration of CysC during the early symptomatic SOD1G93A mice extended their survival times. Administered CysC was predominantly distributed in ventral horn neurons including motor neurons, and induced autophagy through AMP-activated kinase activation to reduce the amount of insoluble mutant SOD1 species. Moreover, PGC-1α, a disease modifier of ALS, was restored by CysC through AMP-activated kinase activation. Finally, the administration of CysC also promoted aggregation of CysC in motor neurons, which is similar to Bunina bodies. Taken together, our findings suggest that CysC represents a promising therapeutic candidate for ALS. Accumulation of disease-linked proteins is implicated in the pathomechanism for neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). This study identified Cystatin C (CysC) as a novel therapeutic target for ALS. Administration of CysC extended the lifespan of SOD1-linked ALS model mice through activating AMP-activated kinase signaling to enhance degradation of mutant SOD1 proteins, and to induce PGC-1 α for promoting neuroprotective signaling. Our findings indicate that CysC is a novel promising therapeutic target for ALS.
Datum: 07.02.2018


Elemental fingerprint as a cerebrospinal fluid biomarker for the diagnosis of Parkinson's disease

The diagnosis of Parkinson's disease (PD) still lacks objective diagnostic markers independent of clinical criteria. Cerebrospinal fluid (CSF) samples from 36 PD and 42 age-matched control patients were subjected to inductively coupled plasma-sector field mass spectrometry and a total of 28 different elements were quantified. Different machine learning algorithms were applied to the dataset to identify a discriminating set of elements yielding a novel biomarker signature. Using 19 stably-detected elements, the extreme gradient tree boosting model showed the best performance in the discrimination of PD and control patients with high specificity and sensitivity (78.6% and 83.3%, respectively), re-classifying the training data to 100%. The 10 times 10-fold cross validation yielded a good AUROC of 0.83. Arsenic, magnesium and selenium all showed significantly higher mean CSF levels in the PD group compared to the control group (p = 0.01, p = 0.04 and p = 0.03). Reducing the number of elements to a discriminating minimum, we identified an elemental cluster (Se, Fe, As, Ni, Mg, Sr), which most importantly contributed to the sample discrimination. Selenium was identified as the element with the highest impact within this cluster directly followed by iron. After prospective validation, this elemental fingerprint in the CSF could have the potential to be used as independent biomarker for the diagnosis of PD. Next to their value as a biomarker, this data also argues for a prominent role of these highly discriminating six elements in the pathogenesis of PD. This article is protected by copyright. All rights reserved.
Datum: 01.02.2018


G5G2.5 core-shell tecto-dendrimer specifically targets reactive glia in brain ischemia

Secondary neuronal death is a serious stroke complication. This process is facilitated by the conversion of glial cells to the reactive pro-inflammatory phenotype that induces neurodegeneration. Therefore, regulation of glial activation is a compelling strategy to reduce brain damage after stroke. However, drugs have difficulties to access the CNS, and to specifically target glial cells. In the present work, we explored the use core-shell polyamidoamine tecto-dendrimer (G5G2.5 PAMAM) and studied its ability to target distinct populations of stroke-activated glial cells. We found that G5G2.5 tecto-dendrimer is actively engulfed by primary glial cells in a time- and dose-dependent manner showing high cellular selectivity and lysosomal localization. In addition, oxygen-glucose deprivation or lipopolysaccharides exposure in vitro and brain ischemia in vivo increase glial G5G2.5 uptake; not being incorporated by neurons or other cell types. We conclude that G5G2.5 tecto-dendrimer is a highly suitable carrier for targeted drug delivery to reactive glial cells in vitro and in vivo after brain ischemia. Regulation of glial activation is a compelling strategy to reduce brain damage after stroke. However, drugs have difficulties to access the central nervous system (CNS), and to specifically target glial cells. In the present work, we show that the core-shell polyamidoamine tecto-dendrimer (FITC-G5G2.5) is avidly incorporated into primary microglia and astroglia. Moreover, astrocyte uptake increases when the culture is exposed to oxygen and glucose deprivation (OGD), an in vitro model of ischemia. Importantly, neurons do not incorporate the tecto-dendrimer under any circumstances. In vivo, brain ischemia induces the G5G2.5 nanoparticle uptake by glial cells. Thus, we propose that G5G2.5 is a highly suitable nanoparticle for reactive glial cell-targeted drug or molecule delivery in vitro and in vivo.
Datum: 31.01.2018


Purinergic signaling in oligodendrocyte development and function

Myelin, an insulating membrane that enables rapid action potential propagation, is an essential component of an efficient, functional vertebrate nervous system. Oligodendrocytes, the myelinating glia of the central nervous system (CNS), produce myelin throughout the CNS, which requires continuous proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPC). Because myelination is essential for efficient neurotransmission, researchers hypothesize that neuronal signals may regulate the cascade of events necessary for this process. The ability of oligodendrocytes and OPCs to detect and respond to neuronal activity is becoming increasingly appreciated, although the specific signals involved are still a matter of debate. Recent evidence from multiple studies points to purinergic signaling as a potential regulator of oligodendrocyte development and differentiation. Adenosine triphosphate (ATP) and its derivatives are potent signaling ligands with receptors expressed on many populations of cells in the nervous system, including cells of the oligodendrocyte lineage. Release of ATP into the extracellular space can initiate a multitude of signaling events, and these downstream signals are specific to the particular purinergic receptor (or receptors) expressed, and whether enzymes are present to hydrolyze ATP to its derivatives adenosine diphosphate (ADP) and adenosine, each of which can activate their own unique downstream signaling cascades. This review will introduce purinergic signaling in the CNS and discuss evidence for its effects on oligodendrocyte proliferation, differentiation and myelination. We will review sources of extracellular purines in the nervous system and how changes in purinergic receptor expression may be coupled to oligodendrocyte differentiation. We will also briefly discuss purinergic signaling in injury and diseases of the CNS. This article is protected by copyright. All rights reserved.
Datum: 28.01.2018


Reviewer selection biases editorial decisions on manuscripts

Many journals, including the Journal of Neurochemistry, enable authors to list peer reviewers as “preferred” or “opposed” suggestions to the editor. At the Journal of Neurochemistry, the handling editor (HE) may follow recommendations or select non-author-suggested reviewers (non-ASRs). We investigated whether selection of author-suggested reviewers (ASRs) influenced decisions on a paper, and whether differences might be related to a reviewers’, editor's or manuscript's geographical location. In this retrospective analysis, we compared original research articles submitted to the Journal of Neurochemistry from 2013 through 2016, that were either reviewed exclusively by non-ASRs, by at least one ASR, by at least one reviewer marked by the author as “opposed”, or none. Manuscript outcome, reviewer rating of manuscript quality, rating of the reviewers’ performance by the editor (R-score), time to review, and the country of the editor, reviewers and manuscript author were analyzed using non-parametric rank-based comparisons, chi-square (x2) analysis, multivariate linear regression, one-way analysis of variance, and inter-rater reliability determination. Original research articles that had been reviewed by at least one ASR stood a higher chance of being accepted (525/1006 = 52%) than papers that had been reviewed by non-ASRs only (579/1800 = 32%). An article was 2.4 times more likely to be accepted than rejected by an ASR compared to a non-ASR (Pearson's x2(1) = 181.3, p<0.05). At decision, the editor did not simply follow the reviewers’ recommendation but had a balancing role: Rates of recommendation from reviewers for rejection were 11.2% (139/1241) with ASRs vs. 29.0% (1379/4755) with non-ASRs (this is a ratio of 0.39 where 1 means no difference between rejection rates for both groups), whereas the proportion of final decisions to reject was 24.7% (248/1006) vs. 45.7% (822/1800) (a ratio of 0.54, considerably closer to 1). Recommendations by non-ASRs were more favorable for manuscripts from USA/Canada and Europe than for Asia/Pacific or Other countries. ASRs judged North American manuscripts most favorably, and judged papers generally more positively (mean: 2.54 on a 1-5 scale) than did non-ASRs (mean: 3.16) reviewers, whereas time for review (13.28 vs. 13.20 days) did not differ significantly between these groups. We also found that editors preferably assigned reviewers from their own geographical region, but there was no tendency for reviewers to judge papers from their own region more favorably. Our findings strongly confirm a bias towards lower rejection rates when ASRs assess a paper, which led to the decision to abandon the option to recommend reviewers at the Journal of Neurochemistry. This article is protected by copyright. All rights reserved.
Datum: 27.01.2018


Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia

Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R – S1P5R. The drug Gilenya® (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalisation and functional antagonism. Internalisation of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In the current study, we investigated the regulation of pro-inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C-X-C motif chemokine 5 (CXCL5), also known as LIX lipopolysaccharide-induced CXC chemokine), expression were quantified. Results showed pFTY720 attenuated LPS-induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, 1) CXCL5/LIX, 2) C-X-C motif chemokine 10 (CXCL10) also known as interferon gamma-induced protein 10 (IP10), and 3) chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase (SphK) attenuated LPS-induced increases in mRNA levels of all three chemokines, suggesting that LPS-TLR4 (Toll-like receptor 4) signalling may enhance chemokine expression via S1P-S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS-induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia. This article is protected by copyright. All rights reserved.
Datum: 27.01.2018


Wnt is here! Could Wnt signalling be promoted to protect against Alzheimer disease?

This Editorial highlights an article in the current issue by Tapia-Rojas and Inestrosa suggesting that attenuation of Wnt signalling may be a triggering factor for the pathogenesis of Alzheimer disease (AD) in the J20 mouse model of AD. Their study utilises Wnt signalling inhibitors that operate at different points in the signalling pathway. The molecular changes of several key Wnt signaling components are examined, along with a thorough analysis of both the amyloid and tau based pathologies in the mouse brain. Studies focusing on inhibition of Wnt signalling in AD mice have the potential to provide much needed information regarding the pathological mechanisms by which attenuated Wnt signalling impacts on AD. This is an Editorial on ‘Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20-APP transgenic and wild-type mice’ in the current issue of the Journal of Neurochemistry. In the highlighted paper, Tapia-Rojas and Inestrosa blocked Wnt signalling at three points as indicated by the red crosses. The agents used to attenuate signalling were administered to J20 Alzheimer's disease (AD) mice and wild-type mice. The Wnt inhibitor promoted the AD phenotype in J20 mice and led to changes that are relevant to AD in the wild-type mice.
Datum: 26.01.2018


Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20-APP transgenic and wild-type mice

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by aggregates of amyloid-β (Aβ) and phosphorylated tau protein, synaptic dysfunction, and spatial memory impairment. The Wnt signaling pathway has several key functions in the adult brain and has been associated with AD, mainly as a neuroprotective factor against Aβ toxicity and tau phosphorylation. However, dysfunction of Wnt/β-catenin signaling might also play a role in the onset and development of the disease. J20 APPswInd transgenic (Tg) mouse model of AD was treated i.p. with various Wnt signaling inhibitors for 10 weeks during pre-symptomatic stages. Then, cognitive, biochemical and histochemical analyses were performed. Wnt signaling inhibitors induced severe changes in the hippocampus, including alterations in Wnt pathway components and loss of Wnt signaling function, severe cognitive deficits, increased tau phosphorylation and Aβ1–42 peptide levels, decreased Aβ42/Aβ40 ratio and Aβ1–42 concentration in the cerebral spinal fluid, and high levels of soluble Aβ species and synaptotoxic oligomers in the hippocampus, together with changes in the amount and size of senile plaques. More important, we also observed severe alterations in treated wild-type (WT) mice, including behavioral impairment, tau phosphorylation, increased Aβ1–42 in the hippocampus, decreased Aβ1–42 in the cerebral spinal fluid, and hippocampal dysfunction. Wnt inhibition accelerated the development of the pathology in a Tg AD mouse model and contributed to the development of Alzheimer's-like changes in WT mice. These results indicate that Wnt signaling plays important roles in the structure and function of the adult hippocampus and suggest that inhibition of the Wnt signaling pathway is an important factor in the pathogenesis of AD. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14276. Wnt signaling plays a role in the onset of Alzheimer Disease (AD). We proposed that attenuation of Wnt/β-catenin induced severe hippocampal alterations, accelerating the development of AD hallmarks in the J20 Tg mouse model, increasing Aβ1–42 production and aggregation, tau phosphorylation and memory loss. More important, induce AD-like neuropathological hallmarks in WT mice, increasing the Aβ1–42 concentration, tau phosphorylation, and cognitive impairment. In summary, the loss of Wnt signaling may be a triggering factor for AD pathogenesis. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14276.
Datum: 26.01.2018


Cerebrovascular and Alzheimer disease: fellow travelers or partners in crime?

In this review, we will discuss the progressive decline in cognitive and intellectual performance in late life that has led to great challenges for medical and community services. The term ‘vascular cognitive impairment’ is defined as any cognitive impairment that is caused by or associated with vascular factors. It can occur alone or in association with Alzheimer disease. The good news is that because vascular risk factors are treatable, it should be possible to prevent or delay some dementias. Since vascular cognitive impairment may often go unrecognized, many experts recommend screening with brief tests to assess memory, thinking, and reasoning for everyone considered to be at high risk for this disorder. Up to 64% of persons 65 years or older who have experienced a stroke have some degree of cognitive impairment with up to one third developing dementia. Postmortem studies indicate that up to 34% of dementia cases show significant vascular pathology. It suggests that ischemic stroke triggers additional pathophysiological process that may lead to a secondary degenerative process that may interact with Alzheimer disease pathology thus accelerating the ongoing primary neurodegeneration. Mechanisms could include hypoperfusion, hypoxia, and neuroinflammation, one of the links between the two pathologies. Stroke and dementia share the same risk and protective factors. Since stroke interact with dementia of all types it may already be possible to reduce or delay some dementias by a number of interventions known to prevent stroke. This article is part of the Special Issue “Vascular Dementia”. Dementia in elderly individuals is often associated with multiple pathologies. In this review, we focus on findings from a meta-analyses of longitudinal studies that suggest that a quarter of elderly have Alzheimer pathology without cognitive impairment, another quarter have asymptomatic cerebrovascular pathology without cognitive impairment, but that the combination doubles the chances that the individual will develop dementia.
Datum: 25.01.2018


Shared pathological pathways of Alzheimer's disease with specific comorbidities: current perspectives and interventions

Alzheimer's disease (AD) belongs to one of the most multifactorial, complex and heterogeneous morbidity-leading disorders. Despite the extensive research in the field, AD pathogenesis is still at some extend obscure. Mechanisms linking AD with certain comorbidities, namely diabetes mellitus, obesity and dyslipidemia, are increasingly gaining importance, mainly because of their potential role in promoting AD development and exacerbation. Their exact cognitive impairment trajectories, however, remain to be fully elucidated. The current review aims to offer a clear and comprehensive description of the state-of-the-art approaches focused on generating in-depth knowledge regarding the overlapping pathology of AD and its concomitant ailments. Thorough understanding of associated alterations on a number of molecular, metabolic and hormonal pathways, will contribute to the further development of novel and integrated theranostics, as well as targeted interventions that may be beneficial for individuals with age-related cognitive decline. The current review focuses on recent evidence of metabolic and neurodegenerative disorders’ overlapping pathology and delves into limitations and perspectives in the field. Phenotypes predisposing to Alzheimer's disease (AD) involve disrupted glucose homeostasis, insulin and adipokine abnormalities, and dyslipidemias. Holistic and integrated research addressing AD and comorbidities could provide impetus for the development of different interventions and personalized approaches.
Datum: 25.01.2018


Decreased rates of cerebral protein synthesis measured in vivo in a mouse model of Tuberous Sclerosis Complex: unexpected consequences of reduced tuberin

Tuberous Sclerosis Complex (TSC) is an autosomal dominant neurogenetic disorder affecting about 1 in 6,000 people and caused by mutations in either TSC1 or TSC2. This disorder is characterized by increased activity of mammalian target of rapamycin complex 1 (mTORC1), which is involved in regulating ribosomal biogenesis and translation initiation. We measured the effects of Tsc2 haploinsufficiency (Tsc2+/-) in three month old male mice on regional rates of cerebral protein synthesis (rCPS) by means of the in vivo L-[1-14C]leucine method. This quantitative autoradiographic method includes an estimate of the integrated specific activity of the tracer amino acid in brain tissue. The estimate accounts for recycling of unlabeled amino acids from tissue protein breakdown by means of a factor (λ) that was determined in control and Tsc2+/- mice. The value of λ was higher in Tsc2+/- mice, indicating that a greater fraction of leucine in the tissue precursor pool for protein synthesis is derived from the plasma compared to controls, consistent with reduced rates of protein degradation. We determined rCPS in freely-moving, awake male Tsc2+/- and control mice, and we used the determined values of λ in the calculation of rCPS. Unexpectedly, we found that rCPS were significantly decreased in 16 of the 17 brain regions analyzed in Tsc2+/- mice compared to controls. Our results indicate a complex role of mTORC1 in the regulation of cerebral protein synthesis that has not been previously recognized. This article is protected by copyright. All rights reserved.
Datum: 24.01.2018


Iron promotes α-synuclein aggregation and transmission by inhibiting TFEB-mediated autophagosome-lysosome fusion

Recent studies have strongly shown that cell-to-cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α-synuclein remains unclear. Here, we constructed a cell-to-cell transmission model of α-synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl2, and α-synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or overexpression. Our results demonstrated that iron promoted α-synuclein aggregation and transmission by inhibiting autophagosome-lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB (TFEB), a master transcriptional regulator of autophagosome-lysosome fusion, and inhibited its nuclear translocation through activating AKT/mTORC1 signaling. After silencing TFEB, ratios of α-synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was overexpressed, the transmission of α-synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α-synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and α-synuclein, and identify TFEB as not only a potential target for preventing α-synuclein transmission, but also a critical factor for iron-induced α-synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α-synuclein transmission in Parkinson's disease. This article is protected by copyright. All rights reserved.
Datum: 24.01.2018


Adenosine A2A receptors are required for glutamate mGluR5- and dopamine D1 receptor-evoked ERK1/2 phosphorylation in rat hippocampus: involvement of NMDA receptor

Interaction between mGluR5 and NMDA receptors (NMDAR) is vital for synaptic plasticity and cognition. We recently demonstrated that stimulation of mGluR5 enhances NMDAR responses in hippocampus by phosphorylating NR2B(Tyr1472) subunit, and this reaction was enabled by adenosine A2A receptors (A2AR) (J Neurochem, 135, 2015, 714). In this study, by using in vitro phosphorylation and western blot analysis in hippocampal slices of male Wistar rats, we show that mGluR5 stimulation or mGluR5/NMDARs co-stimulation synergistically activate ERK1/2 signaling leading to c-Fos expression. Interestingly, both reactions are under the permissive control of endogenous adenosine acting through A2ARs. Moreover, mGluR5-mediated ERK1/2 phosphorylation depends on NMDAR, which however exhibits a metabotropic way of function, since no ion influx through its ion channel is required. Furthermore, our results demonstrate that mGluR5 and mGluR5/NMDAR-evoked ERK1/2 activation correlates well with the mGluR5/NMDAR-evoked NR2B(Tyr1472) phosphorylation, since both phenomena coincide temporally, are Src dependent, and are both enabled by A2ARs. This indicates a functional involvement of NR2B(Tyr1472) phosphorylation in the ERK1/2 activation. Our biochemical results are supported by electrophysiological data showing that in CA1 region of hippocampus, the theta burst stimulation (TBS)-induced long-term potentiation coincides temporally with an increase in ERK1/2 activation and both phenomena are dependent on the tripartite A2A, mGlu5, and NMDARs. Furthermore, we show that the dopamine D1 receptors evoked ERK1/2 activation as well as the NR2B(Tyr1472) phosphorylation are also regulated by endogenous adenosine and A2ARs. In conclusion, our results highlight the A2ARs as a crucial regulator not only for NMDAR responses, but also for regulating ERK1/2 signaling and its downstream pathways, leading to gene expression, synaptic plasticity, and memory consolidation. Metabotropic glutamate 5 receptors (mGluR5) and N-methyl-d-aspartate receptor (NMDAR) interaction is vital for synaptic plasticity and cognition. mGluR5 and NMDAR synergistically stimulate ERK1/2 (extracellular signal-regulated protein kinase 1/2) phosphorylation in rat hippocampus, requiring the adenosine A2A receptor activation and NR2B(Tyr1472) phosphorylation, which are also required for dopamine D1 receptor-evoked ERK1/2 activation. In line with this, our electrophysiological data show that theta burst stimulation-induced long-term potentiation (LTP) in the hippocampal CA1 region increases ERK1/2 activation and that both phenomena are dependent on the tripartite A2AR, mGluR5, and NMDAR.
Datum: 23.01.2018


Corticotropin-releasing hormone-binding protein is upregulated by brain-derived neurotrophic factor and is secreted in an activity-dependent manner in rat cerebral cortical neurons

A recent study revealed that corticotropin-releasing hormone (CRH) in the cerebral cortex (CTX) plays a regulatory role in emotional behaviors in rodents. Given the functional interaction between brain-derived neurotrophic factor (BDNF) and the CRH-signaling pathway in the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that BDNF may regulate gene expression of CRH and its related molecules in the CTX. Findings of real-time quantitative PCR (RT-qPCR) indicated that stimulation of cultured rat cortical neurons with BDNF led to marked elevations in the mRNA levels of CRH and CRH-binding protein (CRH-BP). The BDNF-induced upregulation of CRH-BP mRNA was attenuated by inhibitors of tyrosine receptor kinase (Trk) and MEK, but not by an inhibitor for PI3K and PLCγ. The upregulation was partially blocked by an inhibitor of lysine-specific demethylase (KDM) 6B. Fluorescent imaging identified the vesicular pattern of pH-sensitive green fluorescent protein-fused CRH-BP (CRH-BP-pHluorin), which co-localized with mCherry-tagged BDNF in cortical neurons. In addition, live-cell imaging detected drastic increases of pHluorin fluorescence in neurites upon membrane depolarization. Finally, we confirmed that tetrodotoxin (TTX) partially attenuated the BDNF-induced upregulation of CRH-BP mRNA, but not that of the protein. These observations indicate the following: In cortical neurons, BDNF led to gene expression of CRH-BP and CRH. TrkB, MEK, presumably ERK, and KDM6B are involved in the BDNF-induced gene expression of CRH-BP, and BDNF is able to induce the upregulation in a neuronal activity-independent manner. It is suggested that CRH-BP is stored into BDNF-containing secretory granules in cortical neurons, and is secreted in response to membrane depolarization. This article is protected by copyright. All rights reserved.
Datum: 22.01.2018


Complex neuroprotective and neurotoxic effects of histone deacetylases

By their ability to shatter quality of life for both patients and caregivers, neurodegenerative diseases are the most devastating of human disorders. Unfortunately, there are no effective or long-terms treatments capable of slowing down the relentless loss of neurons in any of these diseases. One impediment is the lack of detailed knowledge of the molecular mechanisms underlying the processes of neurodegeneration. While some neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis, are mostly sporadic in nature, driven by both environment and genetic susceptibility, many others, including Huntington's disease, Spinocerebellar ataxias and Spinal-bulbar muscular atrophy, are genetically inherited disorders. Surprisingly, given their different roots and etiologies, both sporadic and genetic neurodegenerative disorders have been linked to disease mechanisms involving histone deacetylase (HDAC) proteins, which consists of 18 family members with diverse functions. While most studies have implicated certain HDAC subtypes in promoting neurodegeneration, a substantial body of literature suggests that other HDAC proteins can preserve neuronal viability. Of particular interest, however, is the recent realization that a single HDAC subtype can have both neuroprotective and neurotoxic effects. Diverse mechanisms, beyond transcriptional regulation have been linked to these effects, including deacetylation of non-histone proteins, protein-protein interactions, post-translational modifications of the HDAC proteins themselves and direct interactions with disease proteins. The roles of these HDACs in both sporadic and genetic neurodegenerative diseases will be discussed in the current review. This article is protected by copyright. All rights reserved.
Datum: 22.01.2018


An emerging role of astrocytes in vascular contributions to cognitive impairment and dementia

Vascular contributions to cognitive impairment and dementia (VCID) is understood to be the second most common cause of dementia after Alzheimer's disease, and is also a frequent comorbidity with Alzheimer's disease. While VCID is widely acknowledged as a key contributor to dementia, the mechanistic underpinnings of VCID remain poorly understood. In this review, we address the potential role of astrocytes in the pathophysiology of VCID. The vast majority of the blood vessels in the brain are surrounded by astrocytic end-feet. Given that astrocytes make up a significant proportion of the cells in the brain, and that astrocytes are usually passively connected to one another through gap junctions, we hypothesize that astrocytes are key mediators of cognitive impairment because of cerebrovascular disease. In this review, we discuss the existing body of literature regarding the role of astrocytes at the vasculature in the brain, and the known consequences of their dysfunction, as well as our hypotheses regarding the role astrocytes play in VCID. This article is part of the Special Issue “Vascular Dementia”. We propose that hyperhomocysteinemia (HHcy) results in a pro-inflammatory response at the vasculature, which activates the matrix metalloproteinase MMP9. MMP9 subsequently cleaves the a-b dystroglycan complex, leading to disruption of the astrocytic connection with the vasculature. MMP9 also degrades the dystrophin Dp71 anchoring complex, resulting in the down-regulation of astrocytic end-foot channels. The end result of the end-foot disruption is impaired potassium homeostasis in the brain and impaired neurovascular coupling.
Datum: 22.01.2018


Issue Information


Datum: 19.01.2018


Issue Cover (February 2018)

Front cover: The expression of p75 neurotrophin receptor is elevated in the brain of Alzheimer’s disease patients, suggesting its involvement in this disease. We propose a novel mechanism by which amyloid beta (Aβ) through p75 receptor contributes to a vicious cycle of amyloidogenesis. We found that Aβ can enhance amyloid precursor protein (APP) and beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) phosphorylation, and their association and inclusion in endosomes through a p75-dependent mechanism, leading to further Aβ generation.Cortical neurons were isolated from mouse expressing p75 at early development (P0). The neurons were then cultured on coverslips and stained with rabbit anti-APP (6687) (Alexa-Fluor 488; green) and mouse anti-BACE1 (MAB931) (Cy3; red) at DIV4. Nuclei are stained with DAPI (Blue). The APP/BACE1 colocalization (yellow) was measured in neuronal soma and dendrites. Read the full article ‘p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis’ by K. Saadipour, N. B. Mañucat-Tan, Y. Lim, D. J. Keating, K. S. Smith, J.-h. Zhong, H. Liao, L. Bobrovskaya, Y.-J. Wang, M. V. Chao and X.-F. Zhou (J. Neurochem. 2018, vol. 144(3), pp. 302–317) on doi: 10.1111/jnc.14206
Datum: 19.01.2018


Expression of the purine biosynthetic enzyme phosphoribosyl formylglycinamidine synthase (FGAMS) in neurons

Purines are metabolic building blocks essential for all living organisms on earth. De novo purine biosynthesis occurs in the brain and appears to play important roles in neural development. Phosphoribosyl formylglycinamidine synthase (FGAMS, also known as PFAS or FGARAT), a core enzyme involved in the de novo synthesis of purines, may play alternative roles in viral pathogenesis. To date, no thorough investigation of the endogenous expression and localization of de novo purine biosynthetic enzymes has been conducted in human neurons or in virally infected cells. In this study, we characterized expression of FGAMS using multiple neuronal models. In differentiated human SH-SY5Y neuroblastoma cells, primary rat hippocampal neurons, and in whole mouse brain sections, FGAMS immunoreactivity was distributed within the neuronal cytoplasm. FGAMS immunolabeling in vitro demonstrated extensive distribution throughout neuronal processes. To investigate potential changes in FGAMS expression and localization following viral infection, we infected cells with the human pathogen herpes simplex virus 1 (HSV-1). In infected fibroblasts, FGAMS immunolabeling shifted from a diffuse cytoplasmic location to a mainly perinuclear localization by 12 hours post infection. In contrast, in infected neurons, FGAMS localization showed no discernable changes in the localization of FGAMS immunoreactivity. There were no changes in total FGAMS protein levels in either cell type. Together, these data provide insight into potential purine biosynthetic mechanisms utilized within neurons during homeostasis as well as viral infection. This article is protected by copyright. All rights reserved.
Datum: 16.01.2018


Genetic Removal of eIF2α Kinase PERK in Mice Enables Hippocampal L-LTP Independent of mTORC1 Activity

Characterization of the molecular signaling pathways underlying protein synthesis-dependent forms of synaptic plasticity, such as late long-term potentiation (L-LTP), can provide insights not only into memory expression/maintenance under physiological conditions but also potential mechanisms associated with the pathogenesis of memory disorders. Here, we report in mice that L-LTP failure induced by the mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) inhibitor rapamycin is reversed by brain-specific genetic deletion of PKR-like ER kinase, PERK (PERK KO), a kinase for eukaryotic initiation factor 2α (eIF2α). In contrast, genetic removal of general control non-derepressible-2, GCN2 (GCN2 KO), another eIF2α kinase, or treatment of hippocampal slices with the PERK inhibitor GSK2606414, does not rescue rapamycin-induced L-LTP failure, suggesting mechanisms independent of eIF2α phosphorylation. Moreover, we demonstrate that phosphorylation of eukaryotic elongation factor 2 (eEF2) is significantly decreased in PERK KO mice but unaltered in GCN2 KO mice or slices treated with the PERK inhibitor. Reduction of eEF2 phosphorylation results in increased general protein synthesis, and thus could contribute to the mTORC1-independent L-LTP in PERK KO mice. We further performed experiments on mutant mice with genetic removal of eEF2K (eEF2K KO), the only known kinase for eEF2, and found that L-LTP in eEF2K KO mice is insensitive to rapamycin. These data, for the first time, connect reduction of PERK activity with the regulation of translation elongation in enabling L-LTP independent of mTORC1. Thus, our findings indicate previously unrecognized levels of complexity in the regulation of protein synthesis-dependent synaptic plasticity. This article is protected by copyright. All rights reserved.
Datum: 16.01.2018


Loss of STI1-mediated neuronal survival and differentiation in disease-associated mutations of prion protein

Cellular prion protein (PrPC) is widely expressed and displays a variety of well-described functions in the central nervous system (CNS). Mutations of the PRNP gene are known to promote genetic human spongiform encephalopathies, but the components of gain- or loss-of-function mutations to PrPC remain a matter for debate. Among the proteins described to interact with PrPC is stress inducible protein 1 (STI1), a co-chaperonin that is secreted from astrocytes and triggers neuroprotection and neuritogenesis through its interaction with PrPC. In this work, we evaluated the impact of different PrPC pathogenic point mutations on signaling pathways induced by the STI1-PrPC interaction. We found that some of the pathogenic mutations evaluated herein induce partial or total disruption of neuritogenesis and neuroprotection mediated by mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase A (PKA) signaling triggered by STI1-PrPC engagement. A pathogenic mutant PrPC that lacked both neuroprotection and neuritogenesis activities fail to promote negative dominance upon wild-type PrPC. Also, a STI1-α7-nicotinic acetylcholine receptor-dependent cellular signaling was present in a PrPC mutant that maintained both neuroprotection and neuritogenesis activities similar to what has been previously observed by wild-type PrPC. These results point to a loss-of-function mechanism underlying the pathogenicity of PrPC mutations. This article is protected by copyright. All rights reserved.
Datum: 16.01.2018


A spontaneously immortalized Schwann cell line from aldose reductase-deficient mice as a useful tool for studying polyol pathway and aldehyde metabolism

The increased glucose flux into the polyol pathway via aldose reductase (AR) is recognized as a major contributing factor for the pathogenesis of diabetic neuropathy, whereas little is known about the functional significance of AR in the peripheral nervous system. Spontaneously immortalized Schwann cell lines established from long-term cultures of AR-deficient and normal C57BL/6 mouse dorsal root ganglia and peripheral nerves can be useful tools for studying the physiological and pathological roles of AR. These cell lines, designated as immortalized knockout AR Schwann cells 1 (IKARS1) and 1970C3, respectively, demonstrated distinctive Schwann cell phenotypes, such as spindle-shaped morphology and immunoreactivity to S100, p75 neurotrophin receptor, and vimentin, and extracellular release of neurotrophic factors. Conditioned media obtained from these cells promoted neuronal survival and neurite outgrowth of cultured adult mouse dorsal root ganglia neurons. Microarray and real-time RT-PCR analyses revealed significantly down-regulated mRNA expression of polyol pathway-related enzymes, sorbitol dehydrogenase and ketohexokinase, in IKARS1 cells compared with those in 1970C3 cells. In contrast, significantly up-regulated mRNA expression of aldo-keto reductases (AKR1B7 and AKR1B8) and aldehyde dehydrogenases (ALDH1L2, ALDH5A1, and ALDH7A1) was detected in IKARS1 cells compared with 1970C3 cells. Exposure to reactive aldehydes (3-deoxyglucosone, methylglyoxal, and 4-hydroxynonenal) significantly up-regulated the mRNA expression of AKR1B7 and AKR1B8 in IKARS1 cells, but not in 1970C3 cells. Because no significant differences in viability between these two cell lines after exposure to these aldehydes were observed, it can be assumed that the aldehyde detoxification is taken over by AKR1B7 and AKR1B8 in the absence of AR. Aldose reductase (AR) is involved in the pathogenesis of diabetic neuropathy via activating polyol pathway, whereas it plays a role in aldehyde detoxification. We observed down-regulation of polyol pathway-related enzyme mRNA expression, and up-regulation of aldo-keto reductase and aldehyde dehydrogenase mRNA expression in AR-deficient Schwann cells IKARS1 as compared with those in wild-type Schwann cells 1970C3. The up-regulated enzymes might take over AR detoxifying function.
Datum: 16.01.2018


Defective trafficking of Kv2.1 channels in MPTP-induced nigrostriatal degeneration

Intracellular protein trafficking is tightly regulated, and improper trafficking might be the fundamental provocateur for human diseases including neurodegeneration. In neurons, protein trafficking to and from the plasma membrane affects synaptic plasticity. Voltage-gated potassium channel 2.1 (Kv2.1) is a predominant delayed rectifier potassium (K+) current, and electrical activity patterns of dopamine (DA) neurons within the substantia nigra are generated and modulated by the orchestrated function of different ion channels. The pathological hallmark of Parkinson's disease (PD) is the progressive loss of these DA neurons, resulting in the degeneration of striatal dopaminergic terminals. However, whether trafficking of Kv2.1 channels contributes to PD remains unclear. In this study, we demonstrated that MPTP/MPP+ increases the surface expression of the Kv2.1 channel and causes nigrostriatal degeneration by using a subchronic MPTP mouse model. The inhibition of the Kv2.1 channel by using a specific blocker, guangxitoxin-1E, protected nigrostriatal projections against MPTP/MPP+ insult and thus facilitated the recovery of motor coordination. These findings highlight the importance of trafficking of Kv2.1 channels in the pathogenesis of PD. We propose that MPTP/MPP+, a neurotoxin that triggers the symptoms of Parkinson disease, might act on both forward and reverse trafficking to increase the expression of potassium Kv2.1 channels. Kv2.1 channels participate in MPP+-induced cell apoptosis through increased AMPK phosphorylation and cleaved caspase 3. The Kv2.1 blocker, Guangxitoxin 1E (GxTx-1E), either reduces AMPK phosphorylation or recruits endosomes to remove surface Kv2.1 and then attenuates MPTP/MPP+-induced apoptosis. We believe that blocking Kv2.1 with GxTx-1E might provide a new strategy for the treatment of Parkinson's disease.
Datum: 15.01.2018


Increased acetylcholine and glutamate efflux in the prefrontal cortex following intranasal orexin-A (hypocretin-1)

Orexin/hypocretin neurons of the lateral hypothalamus and perifornical area are integrators of physiological function. Previous work from our laboratory and others has shown the importance of orexin transmission in cognition. Age-related reductions in markers of orexin function further suggest that this neuropeptide may be a useful target for the treatment of age-related cognitive dysfunction. Intranasal administration of orexin-A (OxA) has shown promise as a therapeutic option for cognitive dysfunction. However, the neurochemical mechanisms of intranasal OxA administration are not fully understood. Here, we use immunohistochemistry and in vivo microdialysis to define the effects of acute intranasal OxA administration on: (i) activation of neuronal populations in the cortex, basal forebrain, and brainstem and (ii) acetylcholine (ACh) and glutamate efflux in the prefrontal cortex (PFC) of Fischer 344/Brown Norway F1 rats. Acute intranasal administration of OxA significantly increased c-Fos expression, a marker for neuronal activation, in the PFC and in subpopulations of basal forebrain cholinergic neurons. Subsequently, we investigated the effects of acute intranasal OxA on neurotransmitter efflux in the PFC and found that intranasal OxA significantly increased both ACh and glutamate efflux in this region. These findings were independent from any changes in c-Fos expression in orexin neurons, suggesting that these effects are not resultant from direct activation of orexin neurons. In total, these data indicate that intranasal OxA may enhance cognition through activation of distinct neuronal populations in the cortex and basal forebrain and through increased neurotransmission of ACh and glutamate in the PFC. Orexins are peptides produced in the hypothalamus that influence arousal, feeding and cognition. A small body of literature suggests the utility of intranasal orexin administration for targeting the brain, but the brain regions and neurotransmitters that mediate these effects are not yet clear. Following intranasal orexin-A administration in young rats, we used immunohistochemistry and in-vivo microdialysis to investigate neuronal activation (c-Fos expression) and changes in acetylcholine and glutamate efflux in the prefrontal cortex. We show that intranasal orexin-A increases c-Fos expression in multiple cortical and basal forebrain regions and also significantly increases prefrontal cortical efflux of acetylcholine and glutamate.
Datum: 12.01.2018


Mechanisms of neuroprotection against ischemic insult by stress-inducible phosphoprotein-1/prion protein complex

Stress-inducible phosphoprotein 1 (STI1) acts as a neuroprotective factor in the ischemic brain and its levels are increased following ischemia. Previous work has suggested that some of these STI1 actions in a stroke model depend on the recruitment of bone marrow-derived stem cells to improve outcomes after ischemic insult. However, STI1 can directly increase neuroprotective signaling in neurons by engaging with the cellular prion protein (PrPC) and activating α7 nicotinic acetylcholine receptors (α7nAChR). Given that α7nAChR activation has also been involved in neuroprotection in stroke, it is possible that STI1 can have direct actions on neurons to prevent deleterious consequences of ischemic insults. Here, we tested this hypothesis by exposing primary neuronal cultures to 1-h oxygen-glucose deprivation (OGD) and reperfusion and assessing signaling pathways activated by STI1/PrPC. Our results demonstrated that STI1 treatment significantly decreased apoptosis and cell death in mouse neurons submitted to OGD in a manner that was dependent on PrPC and α7nAChR, but also on the activin A receptor 1 (ALK2), which has emerged as a signaling partner of STI1. Interestingly, pharmacological inhibition of the ALK2 receptor prevented neuroprotection by STI1, while activation of ALK2 receptors by bone morphogenetic protein 4 (BMP4) either before or after OGD was effective in decreasing neuronal death induced by ischemia. We conclude that PrPC/STI1 engagement and its subsequent downstream signaling cascades involving α7nAChR as well as the ALK2 receptor may be activated in neurons by increased levels of STI1. This signaling pathway protects neurons from ischemic insults. Stress-inducible phosphoprotein 1 (STI1) is a secreted co-chaperone that exhibits neuroprotective properties in stroke. However, the mechanisms involved in neuronal protection by STI1 remain unknown. Here, we found that extracellular STI1 decreased apoptosis and cellular death in mouse neurons submitted to ischemic insult by modulating signaling by the prion protein, α7nAChR and activin A receptor 1 (ALK2). Our findings suggest that this pathway may protect neurons from ischemic insults during stroke.
Datum: 12.01.2018


White matter degeneration in vascular and other ageing-related dementias

Advances in neuroimaging have enabled greater understanding of the progression of cerebral degenerative processes associated with ageing-related dementias. Leukoaraiosis or rarefied white matter (WM) originally described on computed tomography is one of the most prominent changes which occurs in older age. White matter hyperintensities (WMH) evident on magnetic resonance imaging have become commonplace to describe WM changes in relation to cognitive dysfunction, types of stroke injury, cerebral small vessel disease and neurodegenerative disorders including Alzheimer's disease. Substrates of WM degeneration collectively include myelin loss, axonal abnormalities, arteriolosclerosis and parenchymal changes resulting from lacunar infarcts, microinfarcts, microbleeds and perivascular spacing. WM cells incorporating astrocytes, oligodendrocytes, pericytes and microglia are recognized as key cellular components of the gliovascular unit. They respond to ongoing pathological processes in different ways leading to disruption of the gliovascular unit. The most robust alterations involve oligodendrocyte loss and astrocytic clasmatodendrosis with displacement of the water channel protein, aquaporin 4. These modifications likely precede arteriolosclerosis and capillary degeneration and involve tissue oedema, breach of the blood–brain barrier and induction of a chronic hypoxic state in the deep WM. Several pathophysiological mechanisms are proposed to explain how WM changes commencing with haemodynamic changes within the vascular system impact on cognitive dysfunction. Animal models simulating cerebral hypoperfusion in man have paved the way for several translational opportunities. Various compounds with variable efficacies have been tested to reduce oxidative stress, inflammation and blood–brain barrier damage in the WM. Our review demonstrates that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment. This article is part of the Special Issue “Vascular Dementia”. In this review, we discuss disintegration of the cellular components of the gliovascular unit in the white matter. This has consequences on blood–brain barrier integrity and is a strong correlate of white matter damage associated with cognitive impairment. Animal models of cerebral hypoperfusion replicate several features of white matter changes in man. They have been valuable in identifying various agents which target oxidative stress, inflammation and BBB damage.
Datum: 10.01.2018


In vitro effect of antiretroviral drugs on cultured primary astrocytes: analysis of neurotoxicity and matrix metalloproteinase inhibition

There is little information available on the possible toxic effects that antiretroviral (ARV) drugs used for the treatment of human immunodeficiency virus (HIV)-infected subjects, may have on the central nervous system (CNS) resident cells. Moreover, it remains unclear whether the efficacy of the ARV drugs may also be due to their ability to exert extravirological effects on factors responsible for the development of HIV brain injury, e.g., matrix metalloproteinases (MMPs). This study investigates the toxicity of three different ARV drugs and on their ability to modulate levels and expression of gelatinases A (MMP-2) and B (MMP-9) in astrocytes. Primary cultures of rat astrocytes were activated by exposure to lipopolysaccaride (LPS) and simultaneously treated with darunavir, maraviroc, or raltegravir, used alone or in combination. Among the tested drugs, maraviroc was the less toxic for astrocytes. At toxic concentration (TC50), the studied drugs induced the production of reactive oxygen species (ROS), suggesting that the oxidative stress may represent a mechanism of ARV toxicity. As assessed by gelatin zymography and RT-PCR, the single antiretroviral drugs reduced levels and expression of both MMP-2 and MMP-9 through the inhibition of the signaling transduction pathway of extracellular signal-regulated kinase1/2, which is involved in the regulation of MMP-9 gene. A synergistic inhibition of MMP-2 and MMP-9 was observed with combinations of the studied ARV drugs. The present results indicate that maraviroc, darunavir, and raltegravir, through their ability to inhibit MMP-2 and MMP-9 at doses non-toxic for astrocytes, might have a great potential for the management of HIV-associated neurological complications. The potential impact of long-term exposure to antiretroviral (ARV) drugs on the HIV-neurological impairment is an area of active investigation. We provided evidence that the ARVs darunavir, raltegravir, and maraviroc are not toxic ‘in vitro’ for astrocytes and inhibit the production of matrix metalloproteinases (MMP)-2 and -9 through inhibition of ERK signaling pathway, which is involved in the regulation of MMP gene. These results might have a great potential for the management of HIV-associated neurological complications.
Datum: 10.01.2018


The Role of Glutamate Signaling in Incentive Salience: Second-by-second Glutamate Recordings in Awake Sprague Dawley Rats

The attribution of incentive salience to reward-predictive stimuli has been shown to be associated with substance abuse-like behavior such as increased drug taking. Evidence suggests that glutamate neurotransmission and sequential N-methyl-D-aspartate (NMDA) activation are involved in the attribution of incentive salience. Here we further explore the role of second-by-second glutamate neurotransmission in the attribution of incentive salience to reward-predictive stimuli by measuring sign-tracking behavior during a Pavlovian conditioned approach procedure using ceramic-based microelectrode arrays configured for sensitive measures of extracellular glutamate in awake behaving Sprague Dawley rats. Specifically, we show that there is an increase in extracellular glutamate levels in the prelimbic cortex (PrL) and the nucleus accumbens core (NAcC) during sign-tracking behavior to a food-predictive conditioned stimulus (CS+) compared to the presentation of a non-predictive conditioned stimulus (CS-). Further, the results indicate greater increases in extracellular glutamate levels in the PrL compared to NAcC in response to the CS+, including differences in glutamate release and signal decay. Taken together, the present research suggests that there is differential glutamate signaling in the NAcC and PrL during sign-tracking behavior to a food-predictive CS+. This article is protected by copyright. All rights reserved.
Datum: 08.01.2018


HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity

Parkinson's disease (PD) is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra (SN) and iron accumulation in the substantia nigra. The driver underlying iron accumulation is unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for PD. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants. This article is protected by copyright. All rights reserved.
Datum: 08.01.2018


Parkinson disease-related DJ-1 modulates the expression of uncoupling protein 4 against oxidative stress

Loss of function mutations of DJ-1 (PARK7) have been linked to the pathogenesis of Parkinson disease (PD). Antioxidative stress is one of the multi-protective functions of DJ-1, and oxidation of cysteine 106 (Cys106) has been proposed to regulate the protective activity of DJ-1. Uncoupling protein 4 (UCP4) is located in the inner membrane of mitochondria and functions to protect against oxidative stress. In this study, we used neuronal (SH-SY5Y) cells and DJ-1 knockout (KO) mice to elucidate whether DJ-1 regulated oxidative stress via modulating the expression of UCP4, and the underlying mechanism. The downstream products of oxidative stress, mitochondrial membrane potential (ΔΨm) and cell viability were also investigated. We found that UCP4 was up regulated upon 1-methyl-4-phenylpyridinium (MPP+) stimulation in SH-SY5Y cells, which was enhanced by wild type DJ-1 and alleviated by DJ-1 knockdown. Expression of UCP4 in DJ-1 KO mice was lower compared with wild type mice. In addition, up-regulation of UCP4 was alleviated by inhibition of oxidized DJ-1, and enhanced by increase of oxidized DJ-1 under conditions of oxidative stress using western blot analysis. Moreover, overexpression of UCP4 in DJ-1 knockdown cells partially reversed the decrease of cell viability, ΔΨm, as well as the increase of products of oxidative stress upon MPP+ stimulation. Further analysis showed that DJ-1 regulated transcriptional activity of UCP4 partially via Nuclear factor-kappa B (NF-κB) pathway in the presence of MPP+. Together, our results suggested DJ-1 might regulate the expression of UCP4 by oxidation of DJ-1 and partially via NF-κB pathway in its protective response to oxidative stress. This article is protected by copyright. All rights reserved.
Datum: 08.01.2018


Faim2 contributes to neuroprotection by erythropoietin in transient brain ischemia

Delayed cell death in the penumbra region of acute ischemic stroke occurs through apoptotic mechanisms, making it amenable to therapeutic interventions. Fas/CD95 mediates apoptotic cell death in response to external stimuli. In mature neurons, Fas/CD95 signaling is modulated by Fas-apoptotic inhibitory molecule 2 (Faim2), which reduces cell death in animal models of stroke, meningitis, and Parkinson disease. Erythropoietin (EPO) has been studied as a therapeutic strategy in ischemic stroke. Erythropoietin stimulates the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway, which regulates Faim2 expression. Therefore, upregulation of Faim2 may contribute to neuroprotection by EPO. Male Faim2 deficient mice (Faim2-/-) and wild type littermates (WT) were subjected to 30 min of middle cerebral artery occlusion (MCAo) followed by 72 h of reperfusion. EPO was applied before (30 min) and after (24 and 48 h) MCAo. In WT mice application of EPO at a low dose (5,000 U/kg) significantly reduced stroke volume whereas treatment with high dose (90,000 U/kg) did not. In Faim2-/- animals administration of low dose EPO did not result in a significant reduction of stroke volume. Faim2 expression as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) increased after low dose EPO but not with high dose. An extensive phenotyping including analysis of cerebral vessel architecture did not reveal confounding differences between the genotypes. In human post mortem brain Faim2 displayed a differential expression in areas of penumbral ischemia. Faim2 upregulation may contribute to the neuroprotective effects of low dose erythropoietin in transient brain ischemia. The dose-dependency may explain mixed effects of erythropoietin observed in clinical stroke trials. This article is protected by copyright. All rights reserved.
Datum: 08.01.2018


The ameliorative effect of fluoxetine on neuroinflammation induced by sleep deprivation

It is well known that sleep disorders are harmful to people's health and performance, and growing evidence suggests that sleep deprivation (SD) can trigger neuroinflammation in the brain. The nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome is reported to be relevant to the neuroinflammation induced by SD, but the regulatory signaling that governs the NLRP3 inflammasome in SD is still unknown. Meanwhile, whether the regulatory action of antidepressants in astrocytes could affect the neuroinflammation induced by SD also remains obscure. In this study, we were the first to discover that the antidepressant fluoxetine, a type of specific serotonin reuptake inhibitor widely used in clinical practice, could suppress the neuroinflammation and neuronal apoptosis induced by SD. The main findings from this study are as follows: (i) SD stimulated the expression of activated NLRP3 inflammasomes and the maturation of IL-1β/18 via suppressing the phosphorylation of STAT3 in astrocytes; (ii) SD decreased the activation of AKT and stimulated the phosphorylation of GSK-3β, which inhibited the phosphorylation of STAT3; (iii) the NLRP3 inflammasome expression stimulated by SD was partly mediated by the P2X7 receptor; (iv) an agonist of STAT3 could significantly abolish the expression of NLRP3 inflammasomes induced by an agonist of the P2X7 receptor in primary cultured astrocytes; (v) the administration of fluoxetine could reverse the stimulation of NLRP3 inflammasome expression and function by SD through elevating the activation of STAT3. In conclusion, our present research suggests the promising possibility that fluoxetine could ameliorate the neuronal impairment induced by SD. Sleep disorder is harmful to people's health and sleep deprivation (SD) is reported to induce neuroinflammation in brain. We found that SD could increase the expression of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome via inhibiting the activation of STAT3 in astrocytes. Additionally, it was found that antidepressant fluoxetine could suppress the neuroinflammation and neuronal apoptosis induced by SD via stimulating the phosphorylation of STAT3 in astrocytes. Based on these results, we suggest that fluoxetine could be used for improving the neuronal impairment induced by SD.
Datum: 08.01.2018


Suppression of oxidative phosphorylation confers resistance against bevacizumab in experimental glioma

Although bevacizumab initially shows high response rates in gliomas and other tumours, therapy resistance usually develops later. Because anti-angiogenic agents are supposed to induce hypoxia, we asked whether rendering glioma cells independent of oxidative phosphorylation modulates their sensitivity against hypoxia and bevacizumab. LNT-229 glioma cells without functional mitochondria (rho0) and control (rho+) cells were generated. LNT-229 rho0-cells displayed reduced expression of oxidative phosphorylation-related genes and diminished oxygen consumption. Conversely, glycolysis was up-regulated in these cells, as shown by increased lactate production and stronger expression of glucose transporter-1 and lactate dehydrogenase-A. However, hypoxia-induced cell death in vitro was nearly completely abolished in the LNT-229 rho0-cells, these cells were more sensitive towards glucose restriction and the treatment with the glycolysis inhibitor 2-deoxy-D-glucose. In an orthotopic mouse xenograft experiment, bevacizumab induced hypoxia as reflected by elevated Hypoxia-inducible factor 1-alpha staining in both, rho+- and rho0-tumours. However, it prolonged survival only in the mice bearing rho+-tumours (74 days vs. 105 days, p = 0.024 log-rank test) and had no effect on survival in mice carrying LNT-229 rho0-tumours (75 days vs. 70 days, p = 0.52 log-rank test). Interestingly, inhibition of glycolysis in vivo with 2-deoxy-D-glucose re-established sensitivity of rho0-tumours against bevacizumab (98 days vs. 80 days, p = 0.0001). In summary, ablation of oxidative phosphorylation in glioma cells leads to a more glycolytic and hypoxia-resistant phenotype and is sufficient to induce bevacizumab-refractory tumours. These results add to increasing evidence that a switch towards glycolysis is one mechanism how tumour cells may evade anti-angiogenic treatments and suggest anti-glycolytic strategies as promising approaches to overcome bevacizumab resistance. Since there is growing evidence that a switch to glycolysis is one mechanism to evade anti-angiogenic treatments, we asked whether ablation of oxidative phosphorylation is sufficient to induce bevacizumab resistance in glioma. LNT-229 cells without functional mitochondria (rho0 cells) had a glycolytic phenotype and reduced reactive oxygen species. Hypoxia-induced cell death in vitro was nearly abolished in rho0 cells. Mice carrying rho0-tumours were resistant against bevacizumab, additional treatment with the glycolysis inhibitor 2-deoxy-D-glucose re-established their sensitivity. Our results suggest that independency of oxidative phophorylation is sufficient to induce resistance against bevacizumab, and inhibition of glycolysis might be a therapeutic approach.
Datum: 08.01.2018


Kinetic modeling of [18F]VAT, a novel radioligand for PET imaging vesicular acetylcholine transporter (VAChT) in nonhuman primate brain

Molecular imaging of vesicular acetylcholine transporter (VAChT) in the brain provides an important cholinergic biomarker for the pathophysiology and treatment of dementias including Alzheimer's disease (AD). In this study, kinetics modeling methods were applied and compared for quantifying regional brain uptake of the VAChT-specific PET radiotracer, ((-)-(1-(-8-(2-fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone) ([18F]VAT) in macaques. Total volume distribution (VT) estimates were compared for one-tissue compartment model (1TCM), two-tissue compartment model (2TCM), Logan graphic analysis (LoganAIF) and multiple linear analysis (MA1) with arterial blood input function using data from three macaques. Using the cerebellum-hemispheres as the reference region with data from seven macaques, three additional models were compared: reference tissue model (RTM), simplified reference tissue model (SRTM), and Logan graphic analysis (LoganREF). Model selection criterion (MSC) indicated that a) 2TCM and SRTM were the most appropriate kinetics models for [18F]VAT; and b) SRTM was strongly correlated with 2TCM (Pearson's coefficients r > 0.93, p < 0.05). Test-retest studies demonstrated that [18F]VAT has good reproducibility and reliability (TRV < 10%, ICC > 0.72). These studies demonstrate [18F]VAT is a promising VAChT PET tracer for quantitative assessment of VAChT levels in the brain of living subjects. This article is protected by copyright. All rights reserved.
Datum: 06.01.2018


Chemical hypoxia-induced integrated stress response activation in oligodendrocytes is mediated by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2)

The extent of remyelination in multiple sclerosis lesions is often incomplete. Injury to oligodendrocyte progenitor cells can be a contributing factor for such incomplete remyelination. The precise mechanisms underlying insufficient repair remain to be defined, but oxidative stress appears to be involved. Here, we used immortalized oligodendrocyte cell lines as model systems to investigate a causal relation of oxidative stress and endoplasmic reticulum stress signaling cascades. OLN93 and OliNeu cells were subjected to chemical hypoxia by blocking the respiratory chain at various levels. Mitochondrial membrane potential and oxidative stress levels were quantified by flow cytometry. Endoplasmic reticulum stress was monitored by the expression induction of activating transcription factor 3 and 4 (Atf3, Atf4), DNA damage-inducible transcript 3 protein (Ddit3), and glucose-regulated protein 94. Lentiviral silencing of nuclear factor (erythroid-derived 2)-like 2 or kelch-like ECH-associated protein 1 was applied to study the relevance of NRF2 for endoplasmic reticulum stress responses. We demonstrate that inhibition of the respiratory chain induces oxidative stress in cultured oligodendrocytes which is paralleled by the expression induction of distinct mediators of the endoplasmic reticulum stress response, namely Atf3, Atf4, and Ddit3. Atf3 and Ddit3 expression induction is potentiated in kelch-like ECH-associated protein 1-deficient cells and absent in cells lacking the oxidative stress-related transcription factor NRF2. This study provides strong evidence that oxidative stress in oligodendrocytes activates endoplasmic reticulum stress response in a NRF2-dependent manner and, in consequence, might regulate oligodendrocyte degeneration in multiple sclerosis and other neurological disorders. Degeneration of oligodendrocyte progenitor cells contributes to neurodegeneration, however, underlying mechanisms are unknown. Chemical hypoxia induces loss of mitochondrial membrane potential (A). ‘Leaky’ electrons escape from the respiratory chain and reduce O2, resulting in the generation of superoxide (B). In consequence, NRF2 translocates into the nucleus, where it binds to the antioxidant response element (ARE), thereby activating the transcription of Atf3 and Ddit3 (C). We show that oxidative stress in oligodendrocytes activates endoplasmic reticulum stress responses in a NRF2-dependent manner.
Datum: 05.01.2018


CART peptide in the nucleus accumbens shell inhibits cocaine-induced locomotor sensitization to transient overexpression of α-Ca2+/Calmodulin-dependent Protein Kinase II

Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine-induced locomotor activity when injected into the nucleus accumbens (NAc). Our previous work first confirmed that the inhibitory mechanism of the CART peptide on cocaine-induced locomotor activity is related to a reduction in cocaine-enhanced phosphorylated Ca2+/calmodulin-dependent protein kinaseIIα (pCaMKIIα) and the enhancement of cocaine-induced D3R function. The present study investigated whether CART peptide inhibited cocaine-induced locomotor activity via inhibition of interactions between pCaMKIIα and the D3 dopamine receptor (D3R). We demonstrated that lentivirus-mediated gene transfer transiently increased pCaMKIIα expression, which peaked at 10 days after microinjection into the rat NAc shell, and induced a significant increase in Ca2+ influx along with greater behavioral sensitivity in the open field test after intraperitoneal injections of cocaine (15 mg/kg). However, western blot analysis and coimmunoprecipitation demonstrated that CART peptide treatment in lentivirus-transfected CaMKIIα-overexpressing NAc rat tissues or cells prior to cocaine administration inhibited the cocaine-induced Ca2+ influx and attenuated the cocaine-increased pCaMKIIα expression in lentivirus-transfected CaMKIIα-overexpressing cells. CART peptide decreased the cocaine-enhanced phosphorylated cAMP response element binding protein (pCREB) expression via inhibition of the pCaMKIIα-D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirus-transfected CaMKIIα-overexpressing cells. These results provide strong evidence for the inhibitory modulation of CART peptide in cocaine-induced locomotor sensitization. This article is protected by copyright. All rights reserved.
Datum: 04.01.2018


Triheptanoin protects against status epilepticus-induced hippocampal mitochondrial dysfunctions, oxidative stress and neuronal degeneration

Triheptanoin, the triglyceride of heptanoate, is anaplerotic (refills deficient tricarboxylic acid cycle intermediates) via the propionyl-CoA carboxylase pathway. It has been shown to be neuroprotective and anticonvulsant in several models of neurological disorders. Here, we investigated the effects of triheptanoin against changes of hippocampal mitochondrial functions, oxidative stress and cell death induced by pilocarpine-induced status epilepticus (SE) in mice. Ten days of triheptanoin pre-treatment did not protect against SE, but it preserved hippocampal mitochondrial functions including state 2, state 3 ADP, state 3 uncoupled respiration, respiration linked to ATP synthesis along with the activities of pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex 24 h post-SE. Triheptanoin prevented the SE-induced reductions of hippocampal mitochondrial superoxide dismutase activity and plasma antioxidant status as well as lipid peroxidation. It also reduced neuronal degeneration in hippocampal CA1 and CA3 regions 3 days after SE. In addition, heptanoate significantly reduced hydrogen peroxide-induced cell death in cultured neurons. In situ hybridization localized the enzymes of the propionyl-CoA carboxylase pathway, specifically Pccα, Pccβ and methylmalonyl-CoA mutase to adult mouse hippocampal pyramidal neurons and dentate granule cells, indicating that anaplerosis may occur in neurons. In conclusion, triheptanoin appears to have anaplerotic and antioxidant effects which contribute to its neuroprotective properties. Triheptanoin is anaplerotic via the propionyl-CoA carboxylase (PCC) pathway and has been shown to be neuroprotective and anticonvulsant in several models of neurological disorders. We aimed to elucidate the effects of triheptanoin against changes of mitochondrial functions, oxidative stress and neuronal degeneration after pilocarpine-induced status epilepticus (SE). Triheptanoin pre- and post-treatment preserves mitochondrial functions in the hippocampal formations 24 h post-SE. Triheptanoin also improves the antioxidant status in the plasma and brain, consistent with reductions in lipid peroxidation found in the hippocampal formations. Taken together, preservation of mitochondrial functions and antioxidant effects are likely to contribute to the neuroprotective effects of triheptanoin found at 3 days post-SE.
Datum: 04.01.2018


Validated multi-step approach for in vivo recording and analysis of optogenetically-evoked glutamate in the mouse globus pallidus

Precise quantification of extracellular glutamate concentrations upon neuronal activation is crucial for the understanding of brain function and neurological disorders. While optogenetics is an outstanding method for the correlation between distinct neurons and their role in circuitry and behavior, the electrochemically inactive nature of glutamate has proven challenging for recording upon optogenetic stimulations. This difficulty is due to the necessity for using enzyme-coated microelectrodes and the risk for light-induced artifacts. In this study, we establish a method for the combination of in vivo optogenetic stimulation with selective measurement of glutamate concentrations using enzyme-coated multielectrode arrays and amperometry. The glutamatergic subthalamic nucleus (STN), which is the main electrode target site in deep brain stimulation treatment of advanced Parkinson′s disease, has recently proven opotogenetically targetable in Pitx2-Cre-transgenic mice and was here used as model system. Upon stereotactic injection of viral Channelrhodopsin2-eYFP constructs into the STN, amperometric recordings were performed at a range of optogenetic stimulation frequencies in the globus pallidus, the main STN target area, in anaesthetized mice. Accurate quantification was enabled through a multi-step analysis approach based on self-referencing microelectrodes and repetition of the experimental protocol at two holding potentials, which allowed for the identification, isolation and removal of photoelectric and photoelectrochemical artifacts. This study advances the field of in vivo glutamate detection with combined optogenetics and amperometric recordings by providing a validated analysis framework for application in a wide variety of glutamate-based approaches in neuroscience. This article is protected by copyright. All rights reserved.
Datum: 02.01.2018


Protein components of post-synaptic density lattice, a backbone structure for type I excitatory synapses

It is essential to study the molecular architecture of post-synaptic density (PSD) to understand the molecular mechanism underlying the dynamic nature of PSD, one of the bases of synaptic plasticity. A well-known model for the architecture of PSD of type I excitatory synapses basically comprises of several scaffolding proteins (scaffold protein model). On the contrary, ‘PSD lattice’ observed through electron microscopy has been considered a basic backbone of type I PSDs. However, major constituents of the PSD lattice and the relationship between the PSD lattice and the scaffold protein model, remain unknown. We purified a PSD lattice fraction from the synaptic plasma membrane of rat forebrain. Protein components of the PSD lattice were examined through immuno-gold negative staining electron microscopy. The results indicated that tubulin, actin, α-internexin, and Ca2+/calmodulin-dependent kinase II are major constituents of the PSD lattice, whereas scaffold proteins such as PSD-95, SAP102, GKAP, Shank1, and Homer, were rather minor components. A similar structure was also purified from the synaptic plasma membrane of forebrains from 7-day-old rats. On the basis of this study, we propose a ‘PSD lattice-based dynamic nanocolumn’ model for PSD molecular architecture, in which the scaffold protein model and the PSD lattice model are combined and an idea of dynamic nanocolumn PSD subdomain is also included. In the model, cytoskeletal proteins, in particular, tubulin, actin, and α-internexin, may play major roles in the construction of the PSD backbone and provide linker sites for various PSD scaffold protein complexes/subdomains. Precise knowledge of the post-synaptic density (PSD) structure is indispensable for a deep understanding of the molecular mechanism for spine and PSD dynamics during expression of synaptic plasticity. We investigated protein components of PSD lattice, a backbone structure of excitatory PSD. On the basis of this study we propose a ‘PSD lattice-based dynamic nanocolumn’ model for PSD molecular architecture, in which the scaffold protein model and the PSD lattice structure are combined and an idea of dynamic nanocolumn PSD subdomain is included.
Datum: 29.12.2017


Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epilepsy through the induction of Homer1a

Neuronal intrinsic homeostatic scaling-down of excitatory synapse has been implicated in epilepsy pathogenesis to prevent the neuronal circuits from hyperexcitability. Recent findings suggest a role for neuronal PAS domain protein 4 (Npas4), an activity-dependent neuron-specific transcription factor in epileptogenesis, however, the underlying mechanism by which Npas4 regulates epilepsy remains unclear. We herein propose that limbic seizure activity up-regulates Npas4-homer1a signaling in the hippocampus, thereby contributing to epileptogenesis in mice. The expression level of Npas4mRNA was significantly increased after the pentylenetetrazol (PTZ) treatment. Npas4KO mice developed kindling more rapidly than their wild-type littermates. The expression of Homer1a in the hippocampus increased after seizure activity. Npas4 increased Homer1a promoter activity in COS7 cells. The PTZ-stimulated induction of Homer1a was attenuated in the hippocampus of Npas4KO mice. The combination of fluorescence in situ hybridization and immunohistochemical analyses revealed that Homer1amRNA co-localized with the Npas4 protein after the convulsive seizure response. PTZ reduced excitatory synaptic transmission at the associational/commissural fibers-CA3 synapses through the Npas4-mediated down-regulation of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in hippocampal CA3 neurons. The adeno-associated virus (AAV)-mediated expression of Homer1a resulted in lower α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit levels in the hippocampal plasma membrane fraction than in that from AAV-EGFP-transfected Npas4KO mice. The development of kindling was more strongly suppressed in AAV-Homer1a-microinjected Npas4KO mice than in AAV-EGFP-microinjected Npas4KO mice. These results indicate that Npas4 functions as a molecular switch to initiate homeostatic scaling and the targeting of Npas4-Homer1a signaling may provide new approaches for the treatment of epilepsy. We investigated the mechanism by which neuronal PAS domain protein 4 (Npas4) regulates epilepsy using pentylenetetrazol (PTZ)-treated mice. PTZ treatment increased excitatory inputs followed by Npas4 induction in the hippocampus. Npas4 controlled the surface expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPAR) through the introduction of Homer1a. We propose that Npas4 functions as a molecular switch to initiate homeostatic scaling in epilepsy.
Datum: 29.12.2017


Fibroblast growth factor 2 regulates activity and gene expression of human post-mitotic excitatory neurons

Many neuropsychiatric disorders are thought to result from subtle changes in neural circuit formation. We used human embryonic stem cells and induced pluripotent stem cells (hiPSCs) to model mature, post-mitotic excitatory neurons and examine effects of fibroblast growth factor 2 (FGF2). FGF2 gene expression is known to be altered in brain regions of major depressive disorder (MDD) patients and FGF2 has anti-depressive effects in animal models of depression. We generated stable inducible neurons (siNeurons) conditionally expressing human neurogenin-2 (NEUROG2) to generate a homogenous population of post-mitotic excitatory neurons and study the functional as well as the transcriptional effects of FGF2. Upon induction of NEUROG2 with doxycycline, the vast majority of cells are post-mitotic, and the gene expression profile recapitulates that of excitatory neurons within 6 days. Using hES cell lines that inducibly express NEUROG2 as well as GCaMP6f, we were able to characterize spontaneous calcium activity in these neurons and show that calcium transients increase in the presence of FGF2. The FGF2-responsive genes were determined by RNA-Seq. FGF2-regulated genes previously identified in non-neuronal cell types were up-regulated (EGR1, ETV4, SPRY4, and DUSP6) as a result of chronic FGF2 treatment of siNeurons. Novel neuron-specific genes were also identified that may mediate FGF2-dependent increases in synaptic efficacy including NRXN3, SYT2, and GALR1. Since several of these genes have been implicated in MDD previously, these results will provide the basis for more mechanistic studies of the role of FGF2 in MDD. Alterations in fibroblast growth factor (FGF) signaling have been implicated in major depressive disorder (MDD). In this article, human stem cells are differentiated into glutamatergic neurons. FGF2 treatment of these neurons increases activity as determined using calcium imaging. RNAseq studies implicate a number of genes in this regulation of neuronal activity by FGF2 including SYT2, NRXN3, and GALR1.
Datum: 27.12.2017


Dense-core vesicle biogenesis and exocytosis in neurons lacking chromogranins A and B

Chromogranin A and B (Cgs) are considered to be master regulators of cargo sorting for the regulated secretory pathway (RSP) and dense-core vesicle (DCV) biogenesis. To test this, we analyzed the release of neuropeptide Y (NPY)-pHluorin, a live RSP reporter, and the distribution, number, and appearance of DCVs, in mouse hippocampal neurons lacking expression of CHGA and CHGB genes. qRT-PCR analysis showed that expression of other granin family members was not significantly altered in CgA/B−/− neurons. As synaptic maturation of developing neurons depends on secretion of trophic factors in the RSP, we first analyzed neuronal development in standardized neuronal cultures. Surprisingly, dendritic and axonal length, arborization, synapse density, and synaptic vesicle accumulation in synapses were all normal in CgA/B−/− neurons. Moreover, the number of DCVs outside the soma, stained with endogenous marker Secretogranin II, the number of NPY-pHluorin puncta, and the total amount of reporter in secretory compartments, as indicated by pH-sensitive NPY-pHluorin fluorescence, were all normal in CgA/B−/− neurons. Electron microscopy revealed that synapses contained a normal number of DCVs, with a normal diameter, in CgA/B−/− neurons. In contrast, CgA/B−/− chromaffin cells contained fewer and smaller secretory vesicles with a smaller core size, as previously reported. Finally, live-cell imaging at single vesicle resolution revealed a normal number of fusion events upon bursts of action potentials in CgA/B−/− neurons. These events had normal kinetics and onset relative to the start of stimulation. Taken together, these data indicate that the two chromogranins are dispensable for cargo sorting in the RSP and DCV biogenesis in mouse hippocampal neurons. Chromogranin A and B (Cgs) have been implicated in the biogenesis and release of Dense-Core Vesicles (DCVs) in chromaffin cells. Here, we demonstrate that despite the reduction in the number and size of DCVs in chromaffin cells, this phenotype is not reproduced in hippocampal neurons. We conclude that Cgs are not essential for DCVs biogenesis, cargo sorting, and release in hippocampal neurons.
Datum: 27.12.2017


The role of S-nitrosylation of kainate-type of ionotropic glutamate receptor 2 in epilepsy induced by kainic acid

Epilepsy is a chronic brain disease affecting millions of individuals. Kainate receptors, especially kainate-type of ionotropic glutamate receptor 2 (GluK2), play an important role in epileptogenesis. Recent data showed that GluK2 could undergo post-translational modifications in terms of S-nitrosylation (SNO), and affect the signaling pathway of cell death in cerebral ischemia-reperfusion. However, it is unclear whether S-nitrosylation of GluK2 (SNO-GluK2) contributes to cell death induced by epilepsy. Here, we report that kainic acid-induced SNO-GluK2 is mediated by GluK2 itself, regulated by neuronal nitric oxide synthase (nNOS) and the level of cytoplasmic calcium in vivo and in vitro hippocampus neurons. The whole-cell patch clamp recordings showed the influence of SNO-GluK2 on ion channel characterization of GluK2-Kainate receptors. Moreover, immunohistochemistry staining results showed that inhibition of SNO-GluK2 by blocking nNOS or GluK2 or by reducing the level of cytoplasmic calcium-protected hippocampal neurons from kainic acid-induced injury. Finally, immunoprecipitation and western blotting data revealed the involvement of assembly of a GluK2-PSD95-nNOS signaling complex in epilepsy. Taken together, our results showed that the SNO-GluK2 plays an important role in neuronal injury of epileptic rats by forming GluK2-PSD95-nNOS signaling module in a cytoplasmic calcium-dependent way, suggesting a potential therapeutic target site for epilepsy. GluK2 (kainate-type of ionotropic glutamate receptor 2) plays an important role in epileptogenesis. However, the precise mechanisms are still unclear. In this study, kainic acid (KA)-induced SNO-GluK2 has a close connection with nitric oxide (NO) and cytoplasmic Ca2+. Activation of GluK2 by KA causes a progressive increase in cytoplasmic Ca2+, not only facilitating Ca2+ influx via voltage-gated calcium channels (VGCCs) from the extracellular space, but also triggering RyR-dependent calcium-induced calcium release of endoplasmic reticulum (ER). This Ca2+ rise activates nNOS and subsequently leads to S-nitrosylation of GluK2 (SNO-GluK2), promoting the assembling of GluK2-PSD95-nNOS signaling module, and eventually causing neuronal injury and death. These results suggest that SNO-GluK2 may serve as a potential therapeutic target site for epilepsy. KARs, kainate receptors; RyRs, ryanodine receptors; PSD95, post-synaptic density protein 95; nNOS, neuronal nitric oxide synthase; l-Arg, l-Arginine.
Datum: 26.12.2017


Microglia modulation through external vagus nerve stimulation in a murine model of Alzheimer's disease

Chronically activated microglia contribute to the development of neurodegenerative diseases such as Alzheimer's disease (AD) by the release of proinflammatory mediators that compromise neuronal function and structure.. Modulating microglia functions could be instrumental to interfere with disease pathogenesis.. Previous studies have shown an anti-inflammatory effects of acetylcholine (ACh) or norepinephrine (NE), which mainly activate the β-receptors on microglial cells. Non-invasive vagus nerve stimulation (nVNS) is used in treatment of drug resistant depression, which is a risk factor for developing AD. The vagus nerve projects to the brainstem's locus coeruleus (LC) from which noradrenergic fibers reach to the Nucleus Basalis of Meynert (NBM) and widely throughout the brain. Pilot studies showed first signs of cognitive-enhancing effects of nVNS in AD patients. In the present study, the effects of nVNS on mouse microglia cell morphology were analysed over a period of 280 minutes by 2-photon laser scanning in-vivo microscopy. Total branch length, average branch order and number of branches, which are commonly used indicators for the microglial activation state were determined and compared between young and old wild-type and APP/PS1 transgenic mice. Overall, these experiments show strong morphological changes in microglia, from a neurodestructive to a neuroprotective phenotype, following a brief nVNS in aged animals, especially in APP/PS1 animals, while microglia from young animals were morphologically unaffected. This article is protected by copyright. All rights reserved.
Datum: 21.12.2017


The non-peptidic δ-opioid receptor agonist Tan-67 mediates neuroprotection post-ischemically and is associated with altered amyloid precursor protein expression, maturation and processing in mice

Tan-67 is a selective non-peptidic δ-opioid receptor (DOR) agonist that confers neuroprotection against cerebral ischemia/reperfusion (I/R)-caused neuronal injury in pre-treated animals. In this study, we examined whether post-ischemic administration of Tan-67 in stroke mice is also neuroprotective and whether the treatment affects expression, maturation and processing of the amyloid precursor protein (APP). A focal cerebral I/R model in mice was induced by middle cerebral artery occlusion for 1 h and Tan-67 (1.5, 3 or 4.5 mg/kg) was administered via the tail vein at 1 h after reperfusion. Alternatively, naltrindole, a selective DOR antagonist (5 mg/kg), was administered 1 h before Tan-67 treatment. Our results showed that post-ischemic administration of Tan-67 (3 mg/kg or 4.5 mg/kg) was neuroprotective as shown by decreased infarct volume and neuronal loss following I/R. Importantly, Tan-67 improved animal survival and neurobehavioral outcomes. Conversely, naltrindole abolished Tan-67 neuroprotection in infarct volume. Tan-67 treatment also increased APP expression, maturation and processing in the ipsilateral penumbral area at 6 h but decreased APP expression and maturation in the same brain area at 24 h after I/R. Tan-67-induced increase in APP expression was also seen in the ischemic cortex at 24 h following I/R. Moreover, Tan-67 attenuated BACE-1 expression, β-secretase activity and the BACE cleavage of APP in the ischemic cortex at 24 h after I/R, which was abolished by naltrindole. Our data suggest that Tan-67 is a promising DOR-dependent therapeutic agent for treating I/R-caused disorder and that Tan-67-mediated neuroprotection may be mediated via modulating APP expression, maturation and processing, despite an uncertain causative relationship between the altered APP and the outcomes observed. We proposed that post-ischemic administration of Tan-67, a δ-opioid receptor (DOR), agonist, inhibits neuronal injury caused by ischemic stroke. Tan-67-mediated neuroprotection is dependent on DOR activation and is associated with suppression of ischemic stroke-caused alterations of amyloid precursor protein (APP) expression, maturation and processing as well as β-secretase activity. Our results suggest Tan-67 as a promising therapeutic agent for treating ischemic stroke-caused disorder.
Datum: 19.12.2017


Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe×PS1Δe9 transgenic mouse model of Alzheimer's disease

There is increasing evidence linking neuroinflammation to many neurological disorders including Alzheimer's disease (AD); however, its exact contribution to disease manifestation and/or progression is poorly understood. Therefore, there is a need to investigate neuroinflammation in both health and disease. Here, we investigate cognitive decline, neuroinflammatory and other pathophysiological changes in the APPswe×PS1Δe9 transgenic mouse model of AD. Transgenic (TG) mice were compared to C57BL/6 wild type (WT) mice at 6, 12 and 18 months of age. Neuroinflammation was investigated by [18F]DPA-714 positron emission tomography and myo-inositol levels using 1H magnetic resonance spectroscopy (MRS) in vivo. Neuronal and cellular dysfunction was investigated by looking at N-acetylaspartate (NAA), choline-containing compounds, taurine and glutamate also using MRS. Cognitive decline was first observed at 12 m of age in the TG mice as assessed by working memory tests . A significant increase in [18F]DPA-714 uptake was seen in the hippocampus and cortex of 18 m-old TG mice when compared to age-matched WT mice and 6 m-old TG mice. No overall effect of gene was seen on metabolite levels; however, a significant reduction in NAA was observed in 18 m-old TG mice when compared to WT. In addition, age resulted in a decrease in glutamate and an increase in choline levels. Therefore, we can conclude that increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice. These results support the role of neuroinflammation and metabolite alteration in AD and in ageing. Alzheimer's disease is a complex multifactorial disease. We here investigated numerous biomarkers for neuroinflammation and neurodegeneration and cognitive decline using non-invasive techniques (positron emission tomography and Magnetic Resonance Spectroscopy (MRS)) in APPswe×PS1Δe9 mice at 6, 12 and 18 months of age. We demonstrated a progressive decrease in neuronal marker N-Acetyl-Aspartate by MRS at 18 months of age. This was accompanied by an increase in neuroinflammation detected by positron emission tomography imaging at 18 months of age, confirmed by immunohistochemistry for Aβ plaques and markers of neuroinflammation. There was however no significant increase in myo-inositol, a supposedly surrogate marker for gliosis in MRS.
Datum: 15.12.2017


Vitamin C modulates glutamate transport and NMDA receptor function in the retina

Vitamin C (in the reduced form ascorbate or in the oxidized form dehydroascorbate) is implicated in signaling events throughout the central nervous system (CNS). In the retina, a high-affinity transport system for ascorbate has been described and glutamatergic signaling has been reported to control ascorbate release. Here, we investigated the modulatory role played by vitamin C upon glutamate uptake and N-methyl-d-aspartate (NMDA) receptor activation in cultured retinal cells or in intact retinal tissue using biochemical and imaging techniques. We show that both forms of vitamin C, ascorbate or dehydroascorbate, promote an accumulation of extracellular glutamate by a mechanism involving the inhibition of glutamate uptake. This inhibition correlates with the finding that ascorbate promotes a decrease in cell surface levels of the neuronal glutamate transporter excitatory amino acid transporter 3 in retinal neuronal cultures. Interestingly, vitamin C is prone to increase the activity of NMDA receptors but also promotes a decrease in glutamate-stimulated [3H] MK801 binding and decreases cell membrane content of NMDA receptor glutamate ionotropic receptor subunit 1 (GluN1) subunits. Both compounds were also able to increase cAMP response element-binding protein phosphorylation in neuronal nuclei in a glutamate receptor and calcium/calmodulin kinase-dependent manner. Moreover, the effect of ascorbate is not blocked by sulfinpyrazone and then does not depend on its uptake by retinal cells. Overall, these data indicate a novel molecular and functional target for vitamin C impacting on glutamate signaling in retinal neurons. We propose that ascorbate or dehydroascorbate promotes the internalization of excitatory aminoacid transporter type 3 (EAAT3) and thereby decreases glutamate uptake by retinal neurons and promotes the accumulation of extracellular glutamate. This accumulated glutamate is then able to stimulate N-methyl-d-aspartate (NMDA) and/or AMPA/kainate receptors and activate calcium-dependent signaling pathways leading to cAMP response element-binding protein (CREB) phosphorylation.
Datum: 14.12.2017


Arterial stiffness, cognitive impairment and dementia: confounding factor or real risk?

Large artery stiffness is a frequent condition that arises with ageing, and is accelerated by the presence of co-morbidities like hypertension, obesity and diabetes. Although epidemiological studies have indicated an association between arterial stiffness, cognitive impairment and dementia, the precise effects of stiff arteries on the brain remains obscure. This is because, in humans, arterial stiffness is often accompanied by other factors such as age, high blood pressure, atherosclerosis and inflammation, which could themselves damage the brain independently of stiffness. Therefore, the question remains: is arterial stiffness a true risk for cognitive decline? Or, is it a confounding factor? In this review, we provide an overview of arterial stiffness and its impact on brain function based on human and animal studies. We summarize the evidence linking arterial stiffness to cognitive dysfunction and dementia, and discuss the role of new animal models to better understand the mechanisms by which arterial stiffness affects the brain. We close with an overview of treatments to correct stiffness and discuss the challenges to translate them to real patient care. This article is part of the This article is part of the Special Issue “Vascular Dementia” How does arterial stiffness affect the brain? In this review, we discuss animal and human studies indicating that large artery stiffness increases cerebral blood flow (CBF) pulsatility and reactive oxygen species (ROS) production, which disrupt endothelial cell function leading to blood brain barrier (BBB) permeability, CBF impairments, gliosis, neurodegeneration and, ultimately, to cognitive decline. We propose that treating arterial stiffness could be a novel paradigm to protect the brain in populations where stiffness is prominent, such as the elderly and in people with hypertension. This article is part of the Special Issue “Vascular Dementia”. This article is part of the This article is part of the Special Issue “Vascular Dementia”
Datum: 27.11.2017


Does pathology of small venules contribute to cerebral microinfarcts and dementia?

Microinfarcts are small, but strikingly common, ischemic brain lesions in the aging human brain. There is mounting evidence that microinfarcts contribute to vascular cognitive impairment and dementia, but the origins of microinfarcts are unclear. Understanding the vascular pathologies that cause microinfarcts may yield strategies to prevent their occurrence and reduce their deleterious effects on brain function. Current thinking suggests that cortical microinfarcts arise from the occlusion of penetrating arterioles, which are responsible for delivering oxygenated blood to small volumes of tissue. Unexpectedly, pre-clinical studies have shown that the occlusion of penetrating venules, which drain deoxygenated blood from cortex, lead to microinfarcts that appear identical to those resulting from arteriole occlusion. Here we discuss the idea that cerebral venule pathology could be an overlooked source for brain microinfarcts in humans. This article is part of the Special Issue “Vascular Dementia”. We hypothesize that obstructed penetrating venules are a source of cerebral microinfarcts – a small but widespread form of ischemic brain lesion linked to cognitive decline. In this review, we suggest that pathological mechanisms, such as cerebral hypoperfusion, arteriolosclerosis, and cerebral amyloid angiopathy, generate blood flow deficits and thrombosis in cerebral venules, leading to the formation of microinfarcts. This article is part of the Special Issue “Vascular Dementia”.
Datum: 07.11.2017


Screening the expression characteristics of several miRNAs in G93A-SOD1 transgenic mouse: altered expression of miRNA-124 is associated with astrocyte differentiation by targeting Sox2 and Sox9

MicroRNAs (miRNAs) are suspected to be a contributing factor in amyotrophic lateral sclerosis (ALS). Here, we assess the altered expression of miRNAs and the effects of miR-124 in astrocytic differentiation in neural stem cells of ALS transgenic mice. Differentially expressed miRNA-positive cells (including miR-124, miR-181a, miR-22, miR-26b, miR-34a, miR-146a, miR-219, miR-21, miR-200a, and miR-320) were detected by in situ hybridization and qRT-PCR in the spinal cord and the brainstem. Our results demonstrated that miR-124 was down-regulated in the spinal cord and brainstem. In vitro, miR-124 was down-regulated in neural stem cells and up-regulated in differentiated neural stem cells in G93A-superoxide dismutase 1 (SOD1) mice compared with WT mice by qRT-PCR. Meanwhile, Sox2 and Sox9 protein levels showed converse change with miR-124 in vivo and vitro. After over-expression or knockdown of miR-124 in motor neuron-like hybrid (NSC34) cells of mouse, Sox2 and Sox9 proteins were noticeably down-regulated or up-regulated, whereas Sox2 and Sox9 mRNAs remained virtually unchanged. Moreover, immunofluorescence results indicated that the number of double-positive cells of Sox2/glial fibrillary acidic protein (GFAP) and Sox9/glial fibrillary acidic protein (GFAP) was higher in G93A-SOD1 mice compared with WT mice. We also found that many Sox2- and Sox9-positive cells were nestin positive in G93A-SOD1 mice, but not in WT mice. Furthermore, differentiated neural stem cells from G93A-SOD1 mice generated a greater proportion of astrocytes and lower proportion of neurons than those from WT mice. MiR-124 may play an important role in astrocytic differentiation by targeting Sox2 and Sox9 in ALS transgenic mice. MicroRNAs (miRNAs) are suspected to be contributing factors in amyotrophic lateral sclerosis (ALS). We used In situ hybridization (ISH) to map the expression of candidate miRNAs in G93A-SOD1 ALS transgenic mice. miR-124 was selected as the target for further study to explore the underlying mechanisms in ALS. miR-124 may be associated with astrocytic differentiation of neural stem cells through regulation of the expression of Sox2 and Sox9 in G93A-SOD1 ALS mice. Our study offers a new approach to investigate the role of neural stem cells in response to motor neuron degeneration and in the development of ALS.
Datum: 07.11.2017


Cerebral blood flow in normal aging adults: cardiovascular determinants, clinical implications, and aerobic fitness

Senescence is a leading cause of mortality, disability, and non-communicable chronic diseases in older adults. Mounting evidence indicates that the presence of cardiovascular disease and risk factors elevates the incidence of both vascular cognitive impairment and Alzheimer's disease (AD). Age-related declines in cardiovascular function may impair cerebral blood flow (CBF) regulation, leading to the disruption of neuronal micro-environmental homeostasis. The brain is the most metabolically active organ with limited intracellular energy storage and critically depends on CBF to sustain neuronal metabolism. In patients with AD, cerebral hypoperfusion, increased CBF pulsatility, and impaired blood pressure control during orthostatic stress have been reported, indicating exaggerated, age-related decline in both cerebro- and cardiovascular function. Currently, AD lacks effective treatments; therefore, the development of preventive strategy is urgently needed. Regular aerobic exercise improves cardiovascular function, which in turn may lead to a better CBF regulation, thus reducing the dementia risk. In this review, we discuss the effects of aging on cardiovascular regulation of CBF and provide new insights into the vascular mechanisms of cognitive impairment and potential effects of aerobic exercise training on CBF regulation. This article is part of the Special Issue “Vascular Dementia”. We propose that age-related decline of cardiovascular function profoundly alters cerebral blood flow (CBF). The stiffening and wall thickening of central elastic arteries elevate systolic (SBP) and pulse (PP) pressure which subsequently augment CBF pulsatility. The elevated mean arterial pressure (MAP), resulting from increased total peripheral resistance (TPR) and endothelial dysfunction, may induce cerebrovascular remodeling to increase the resistance (CVR) and impedance. The blunted cardiovagal baroreflex sensitivity (BRS) may lead to BP and CBF instability during extrinsic stimuli (e.g., postural change). This article is part of the Special Issue “Vascular Dementia”.
Datum: 07.11.2017


Binswanger's disease: biomarkers in the inflammatory form of vascular cognitive impairment and dementia

Vascular cognitive impairment and dementia (VCID) is a major public health concern because of the increased incidence of vascular disease in the aging population and the impact of vascular disease on Alzheimer's disease. VCID is a heterogeneous group of diseases for which there are no proven treatments. Biomarkers can be used to select more homogeneous populations. Small vessel disease is the most prevalent form of VCID and is the optimal form for treatment trials because there is a progressive course with characteristic pathological changes. Subcortical ischemic vascular disease of the Binswanger type (SIVD-BD) has a characteristic set of features that can be used both to identify patients and to follow treatment. SIVD-BD patients have clinical, neuropsychological, cerebrospinal fluid (CSF) and imaging features that can be used as biomarkers. No one feature is diagnostic, but a multimodal approach defines the SIVD-BD spectrum disorder. The most important features are large white matter lesions with axonal damage, blood–brain barrier disruption as shown by magnetic resonance imaging and CSF, and neuropsychological evidence of executive dysfunction. We have used these features to create a Binswanger Disease Scale and a probability of SIVD-BD, using a machine-learning algorithm. The patients discussed in this review are derived from published studies. Biomarkers not only aid in early diagnosis before the disease process has progressed too far for treatment, but also can indicate response to treatment. Refining the use of biomarkers will allow dementia treatment to enter the era of precision medicine. This article is part of the Special Issue “Vascular Dementia”. Vascular cognitive impairment and dementia (VCID) is a major public health concern because of the increased incidence of vascular disease in the aging population and the impact of vascular disease on Alzheimer's disease. Subcortical ischemic vascular disease of the Binswanger type (SIVD-BD) has a characteristic set of features that can be used both to identify patients and to follow treatment. We have used clinical features to create a Binswanger Disease Scale and a probability of SIVD-BD, using a machine-learning algorithm. Refining the use of biomarkers will allow dementia treatment to enter the era of precision medicine. The schematic shows the matrix metalloprotinase mechanism involved in blood–brain barrier opening in chronic vascular disease. This article is part of the Special Issue “Vascular Dementia”.
Datum: 06.11.2017


Ethanol stimulates the in vivo axonal movement of neuropeptide dense-core vesicles in Drosophila motor neurons

Proper neuronal function requires essential biological cargoes to be packaged within membranous vesicles and transported, intracellularly, through the extensive outgrowth of axonal and dendritic fibers. The precise spatiotemporal movement of these cargoes is vital for neuronal survival and, thus, is highly regulated. In this study we test how the axonal movement of a neuropeptide-containing dense-core vesicle (DCV) responds to alcohol stressors. We found that ethanol induces a strong anterograde bias in vesicle movement. Low doses of ethanol stimulate the anterograde movement of neuropeptide-DCV while high doses inhibit bi-directional movement. This process required the presence of functional kinesin-1 motors as reduction in kinesin prevented the ethanol-induced stimulation of the anterograde movement of neuropeptide-DCV. Furthermore, expression of inactive glycogen synthase kinase 3 (GSK-3β) also prevented ethanol-induced stimulation of neuropeptide-DCV movement, similar to pharmacological inhibition of GSK-3β with lithium. Conversely, inhibition of PI3K/AKT signaling with wortmannin led to a partial prevention of ethanol-stimulated transport of neuropeptide-DCV. Taken together, we conclude that GSK-3β signaling mediates the stimulatory effects of ethanol. Therefore, our study provides new insight into the physiological response of the axonal movement of neuropeptide-DCV to exogenous stressors. Ethanol is a widely abused drug, but detailed physiological and molecular effects of ethanol consumption are only recently being understood. For Drosophila, ethanol is a naturally occurring environmental chemical that elicits behavioral changes making them an ideal model system for studying the effects of ethanol. This study found that, in Drosophila, low doses of ethanol results in the stimulation of neuropeptide vesicle transport with a bias toward the anterograde direction. We propose that this effect is mediated via GSK-3β-mediated modulation of kinesin-1 motor proteins. Thus, modulation of peptideric neurons may underlie the toxic and behavioral effects of ethanol and provide a novel target for therapeutics.
Datum: 18.10.2017


Early-stage attenuation of phase-amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of Alzheimer's disease

Alzheimer's disease (AD) is pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aβ-dependent neuronal dysfunction including modulation of gamma-aminobutyric acid-ergic signaling. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broad repertoire of AD-like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma-aminobutyric acid (GABAA) receptor subunits α1, α5, and δ, and glutamic acid decarboxylases (GAD65 and GAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low-gamma band power was strongly attenuated in the HPC and mPFC of TgF344-AD rats in comparison to those in non-transgenic littermates. In addition, the phase-amplitude coupling of the neuronal networks in both areas was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude in TgF344-AD animals. Finally, the gamma coherence between HPC and mPFC was attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage of AD-like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by Aβ and tau pathologies. This article is part of the Special Issue “Vascular Dementia”. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aβ-dependent neuronal dysfunction including modulation of GABAergic signaling. At 8 months of age, the TgF344-AD rat models of Alzheimer's disease presents Aβ plaques and tau hyperphosphorylation but no cognitive impairments. These animals were found to exhibit decreased phase-amplitude coupling between theta and high-gamma bands in the hippocampus and in the medial prefrontal cortex, accompanied by a reduction in GAD67+ cells in CA1 and CA3 of the hippocampus. This article is part of the Special Issue “Vascular Dementia”.
Datum: 10.10.2017


Effect of a multinutrient intervention after ischemic stroke in female C57Bl/6 mice

Stroke can affect females very differently from males, and therefore preclinical research on underlying mechanisms and the effects of interventions should not be restricted to male subjects, and treatment strategies for stroke should be tailored to benefit both sexes. Previously, we demonstrated that a multinutrient intervention (Fortasyn) improved impairments after ischemic stroke induction in male C57Bl/6 mice, but the therapeutic potential of this dietary treatment remained to be investigated in females. We now induced a transient middle cerebral artery occlusion (tMCAo) in C57Bl/6 female mice and immediately after surgery switched to either Fortasyn or an isocaloric Control diet. The stroke females performed several behavioral and motor tasks before and after tMCAo and were scanned in an 11.7 Tesla magnetic resonance imaging (MRI) scanner to assess brain perfusion, integrity, and functional connectivity. To assess brain plasticity, inflammation, and vascular integrity, immunohistochemistry was performed after killing of the mice. We found that the multinutrient intervention had diverse effects on the stroke-induced impairments in females. Similar to previous observations in male stroke mice, brain integrity, sensorimotor integration and neurogenesis benefitted from Fortasyn, but impairments in activity and motor skills were not improved in female stroke mice. Overall, Fortasyn effects in the female stroke mice seem more modest in comparison to previously investigated male stroke mice. We suggest that with further optimization of treatment protocols more information on the efficacy of specific interventions in stroked females can be gathered. This in turn will help with the development of (gender-specific) treatment regimens for cerebrovascular diseases such as stroke. This article is part of the Special Issue “Vascular Dementia”. The impact of a multinutrient intervention has been investigated on stroke-induced (transient middle cerebral artery occlusion) impairments in female C57Bl/6 mice. Similar to previous observations in male stroke mice, cerebral blood flow, brain integrity, (functional) connectivity, and neurogenesis benefitted from the multinutrient intervention, but in contrast with male stroke mice, impairments in activity and motor skills did not improve in female stroke mice. This article is part of the Special Issue “Vascular Dementia”.
Datum: 10.10.2017


The role of exercise in mitigating subcortical ischemic vascular cognitive impairment

Subcortical ischemic vascular cognitive impairment (SIVCI) is the most preventable form of cognitive dysfunction. There is converging evidence from animal and human studies that indicate vascular injury as the primary cause of SIVCI. Currently, there are no curative pharmaceutical treatments for vascular dementia; however, exercise may be a promising strategy to combat SIVCI. This review will focus on the role of exercise as a strategy to prevent or slow the progression of SIVCI, with particular emphasis on the mechanisms by which exercise may improve cerebrovascular function. We propose that exercise may be an effective strategy to combat SIVCI by improving cognitive function, increasing the bioavailability of neurotrophins, stimulating endothelial function, and controlling vascular risk factors. This article is part of the Special Issue “Vascular Dementia”; Currently, there are no curative pharmaceutical treatments for subcortical ischemic vascular cognitive impairment (SIVCI). However, exercise may combat SIVCI by increasing the bioavailability of neurotrophins, improving cognitive function, stimulating endothelial function, and controlling vascular risk factors. We propose that exercise is a promising strategy to prevent or slow the progression of SIVCI. This article is part of the Special Issue “Vascular Dementia”;
Datum: 27.09.2017


p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Aβ) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aβ. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Aβ and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Aβ and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Aβ and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163. The abnormal production of Aβ, and other neurodegenerative ligands in the brain could serve as a stimulus that can promote activation and expression of p75 neurotrophin receptor in sporadic Alzheimer's disease. In this study, we propose a novel mechanism by which Aβ through p75 neurotrophin receptor contributes to a vicious cycle of amyloidogenesis. We found that Aβ can enhance APP and BACE1 phosphorylation, and their association and inclusion in endosomes through a p75-dependent mechanism, leading to further Aβ generation. Therefore, blocking p75 neurotrophin receptor activity may reduce Aβ-stimulated amyloidogenesis and could be a therapeutic target to attenuate the progression of Alzheimer's disease. Cover Image for this Issue: doi. 10.1111/jnc.14163.
Datum: 27.09.2017


Cerebral amyloid angiopathy as a cause of neurodegeneration

Sporadic, age-related cerebral amyloid angiopathy (CAA) is most commonly recognized clinically as a cause of hemorrhagic stroke and transient focal neurological episodes in older persons. But a growing body of research in the last 5 years shows that the pathophysiology of CAA is much more complex than previously believed, leading to many different types of brain injury. CAA has now been linked with brain atrophy in regions remote from those directly affected by intracerebral hematomas, and with risk for progressive cognitive decline in the absence of new hemorrhagic strokes. Therefore, CAA is associated with features – brain atrophy and progressive cognitive decline – that are typically considered hallmarks of neurodegenerative disease. Although CAA is usually accompanied by some degree of Alzheimer's disease pathology, the profiles of cortical thinning and cognitive impairment do not fully overlap with those seen in Alzheimer's disease, suggesting that there are CAA-specific pathways of neurodegeneration. CAA-related brain ischemia may be an important mechanism that leads to brain injury, cortical disconnection, and cognitive impairment. This article is part of the Special Issue “Vascular Dementia”. Sporadic, age-related cerebral amyloid angiopathy (CAA), caused by vascular Aβ deposition, is most commonly recognized clinically as a cause of hemorrhagic stroke. This review synthesizes emerging evidence that CAA is associated with cardinal features of neurodegeneration – atrophy and cognitive impairment – and highlights multiple pathomechanisms of brain injury that may cause cognitive impairment in this disease. This article is part of the Special Issue “Vascular Dementia”.
Datum: 21.09.2017


Transcriptional profiling of human neural precursors post alcohol exposure reveals impaired neurogenesis via dysregulation of ERK signaling and miR-145

Gestational alcohol exposure causes a range of neuropsychological disorders by modulating neurodevelopmental genes and proteins. The extent of damage depends on the stage of the embryo as well as dosage, duration and frequency of exposure. Here, we investigated the neurotoxic effects of alcohol using human embryonic stem cells. Multiple read-outs were engaged to assess the proliferation and differentiation capacity of neural precursor cells upon exposure to 100 mM ethanol for 48 h corresponding to the blood alcohol levels for binge drinkers. Whole-genome analysis revealed a spatiotemporal dysregulation of neuronal- and glial-specific gene expression that play critical roles in central nervous system (CNS) development. Alterations observed in the transcriptome may be attributed to epigenetic constitution witnessed by differential histone H3 Lys-4/Lys-27 modifications and acetylation status. In-depth mRNA and protein expression studies revealed abrogated extracellular signal-regulated kinases signaling in alcohol-treated cells. Consistent with this finding, ingenuity pathway analysis and micro-RNA profiling demonstrated up-regulation of miR-145 by targeting the neural specifier Sox-2. We also show that the neurite branching complexity of tubulin, beta 3 class III+ neurons was greatly reduced in response to alcohol. Finally, in vivo studies using zebrafish embryos reconfirmed the in vitro findings. Employing molecular endpoints in a human model, this report indicates for the first time that acute alcohol exposure could lead to impaired brain development via perturbation of extracellular signal-regulated kinases pathway and miR-145. However, it still needs to be addressed whether these modulations sustain throughout development, compromising the ability of the individual during adulthood and aging. Gestational alcohol exposure causes a range of neuropsychological disorders, but lack of relevant model poses serious limitations toward understanding such defects. Our data unveil that EtOH perturbs MAPK/ERK signaling accompanied by deregulation of miR-145 targeting the neural specifier Sox-2 causing compromised neuronal complexity resulting in abnormal neurogenesis. Employing molecular endpoints in humanized model, we show for the first time that acute alcohol exposure could lead to impaired brain development.
Datum: 19.09.2017


Dementia risk and prevention by targeting modifiable vascular risk factors

The incidence of dementia is expected to double in the next 20 years and will contribute to heavy social and economic burden. Dementia is caused by neuronal loss that leads to brain atrophy years before symptoms manifest. Currently, no cure exists and extensive efforts are being made to mitigate cognitive impairment in late life in order to reduce the burden on patients, caregivers, and society. The most common type of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) often co-exists in the brain and shares common, modifiable risk factors, which are targeted in numerous secondary prevention trials. There is a growing need for non-pharmacological interventions and infrastructural support from governments to encourage psychosocial and behavioral interventions. Secondary prevention trials need to be redesigned based on the risk profile of individual subjects, which require the use of validated and standardized clinical, biological, and neuroimaging biomarkers. Multi-domain approaches have been proposed in high-risk populations that target optimal treatment; clinical trials need to recruit individuals at the highest risk of dementia before symptoms develop, thereby identifying an enriched disease group to test preventative and disease modifying strategies. The underlying aim should be to reduce microscopic brain tissue loss by modifying vascular and lifestyle risk factors over a relatively short period of time, thus optimizing the opportunity for preventing dementia in the future. Collaboration between international research groups is of key importance to the optimal use and allocation of existing resources, and the development of new techniques in preventing dementia. This article is part of the Special Issue "Vascular Dementia" Vascular risk factors through their interaction with genetic susceptibility and the environment result in vessel wall damage, which leads to chronic hypoperfusion and may exacerbate the accumulation of Aβ. Together these processes cause neuronal dysfunction leading to atrophy, which manifests subclinically or clinically by stroke and small vessel disease on one side, and AD or cerebral amyloid angiopathy on the other. Older persons are most susceptible to AD, VaD or mixed dementia. We propose a multidimensional approach to optimize the opportunity for prevention by focusing on modifying vascular risk factors.
Datum: 06.09.2017


Rho-associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease

The causes of late-onset Alzheimer's disease are unclear and likely multifactorial. Rho-associated protein kinases (ROCKs) are ubiquitously expressed signaling messengers that mediate a wide array of cellular processes. Interestingly, they play an important role in several vascular and brain pathologies implicated in Alzheimer's etiology, including hypertension, hypercholesterolemia, blood–brain barrier disruption, oxidative stress, deposition of vascular and parenchymal amyloid-beta peptides, tau hyperphosphorylation, and cognitive decline. The current review summarizes the functions of ROCKs with respect to the various risk factors and pathologies on both sides of the blood–brain barrier and present support for targeting ROCK signaling as a multifactorial and multi-effect approach for the prevention and amelioration of late-onset Alzheimer's disease. This article is part of the Special Issue “Vascular Dementia”. We reviewed evidence that supports using inhibitors of ROCKs to treat Alzheimer Disease (AD). The multifaceted AD pathologies on both sides of the blood–brain barrier can be ameliorated by inhibition of ROCKs providing a potentially viable therapeutic strategy. This article is part of the Special Issue “Vascular Dementia”.
Datum: 30.08.2017


Prevention of cognitive impairment: scientific guidance and windows of opportunity

Cognitive impairment of later life is an important medical and public health challenge. Worldwide it is estimated that the number of persons with dementia will continue to increase, especially in low- and middle-income countries. An important public health challenge relates to the prevention of cognitive decline and dementia. Specifically, is it possible to maintain cognitive vitality or prevent or slow cognitive decline? In this opinion-based piece, I review United States-based guidance statements for maintenance of cognition and select single and multidomain trials designed to preserve cognitive function. Guidance statements now recommend that we treat or prevent cardiovascular risks in hopes of preventing cognitive impairment or decline. I discuss potential gaps between guidance statements and interventional studies, and provide comments on where windows of opportunity may exist to close potential gaps in our quest to maintain cognitive vitality. This article is part of the Special Issue “Vascular Dementia” Worldwide, dementia prevalence is expected to triple over the next 30 years. Strategies to prevent or slow cognitive decline in older persons have not been successful. More recently, however, we have begun to think more broadly about the antecedents of the dementias of later life and have begun to recognize the importance of modifiable cardiovascular risk factors and the occurrence of coexistent stroke, a preventable condition, in patients with Alzheimer's disease. In this opinion-piece I review United States-based guidance statements for maintenance of cognitive vitality, recent clinical trials to prevent cognitive impairment, and potential gaps in relation to clinical strategies to prevent cognitive impairment. The graphic depicts steps to be taken to preserve cognitive vitality in line with recommendations from the Institute of Medicine report. This article is part of the Special Issue “Vascular Dementia”
Datum: 16.08.2017


 


Category: Current Chemistry Research

Last update: 04.01.2018.






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