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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Journal of Neurochemistry - Abstracts



Corrigendum


Datum: 24.11.2017


The low affinity neurotensin receptor antagonist levocabastine impairs brain nitric oxide synthesis and mitochondrial function by independent mechanisms

Neurotensin is known to inhibit neuronal Na+, K+-ATPase, an effect that is rescued by nitric oxide (NO) synthase inhibition. However, whether the neurotensinergic and the nitrergic systems are independent pathways, or are mechanistically linked, remains unknown. Here, we addressed this issue and found that the administration of low affinity neurotensin receptor (NTS2) antagonist, levocabastine (50 μg/kg, i.p.) inhibited NO synthase (NOS) activity by 74 and 42% after 18 h in synaptosomal and mitochondrial fractions isolated from the Wistar rat cerebral cortex, respectively; these effects disappeared 36 h after levocabastine treatment. Intriguingly, whereas neuronal NOS protein abundance decreased (by 56%) in synaptosomes membranes, it was enhanced (by 86%) in mitochondria 18 h after levocabastine administration. Levocabastine enhanced the respiratory rate of synaptosomes in the presence of oligomycin, but it failed to alter the spare respiratory capacity; furthermore, the mitochondrial respiratory chain (MRC) complexes I–IV activities were severely diminished by levocabastine administration. The inhibition of NOS and MRC complexes activities were also observed after incubation of synaptosomes and mitochondria with levocabastine (1 μM) in vitro. These data indicate that the NTS2 antagonist levocabastine regulates NOS expression and activity at the synapse, suggesting an interrelationship between the neurotensinergic and the nitrergic systems. However, the bioenergetics effects of NTS2 activity inhibition are likely to be independent from the regulation of NO synthesis. Levocabastine effects on nitric oxide synthase and mitochondrial function: The aim of this work was to study a possible relationship between the activity of neurotensin NTS2 receptor and NO synthesis. With this purpose, levocabastine was administered to rats and the activity and the expression of nitric oxide synthase (NOS) together with mitochondrial function were evaluated. Levocabastine treatment inhibits NOS activity after neurotensin NTS2 receptor blockade and/or by a direct action on NOS enzyme, both in synaptic membranes and in mitochondria. Also, mitochondrial respiratory complexes and MAO activity are diminished by levocabastine treatment. Levocabastine effects on NO metabolism and on mitochondrial respiratory chain, may be interpreted as parallel actions rather than interrelated phenomena. The organelles, membrane structure and associated proteins in the scheme are not in scale.
Datum: 24.11.2017


Fibroblast Growth Factor 2 Regulates Activity and Gene Expression of Human Postmitotic Excitatory Neurons

Many neuropsychiatric disorders are thought to result from subtle changes in neural circuit formation. We used human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) to model mature, postmitotic excitatory neurons and examine effects of 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 upregulated (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. This article is protected by copyright. All rights reserved.
Datum: 23.11.2017


Functional properties of dopamine transporter oligomers after copper linking

Although it is universally accepted that dopamine transporters (DATs) exist in monomers, dimers and tetramers (i.e. dimers of dimers), it is not known whether the oligomeric organization of DAT is a prerequisite for its ability to take up dopamine (DA), or whether each DAT protomer-the subunit of quaternary structure- functions independently in terms of DA translocation. In the present work copper phenanthroline (CuP) was used to selectively target surface DAT: increasing concentrations of CuP gradually cross-linked natural DAT dimers in LLC-PK1 cells stably expressing hDAT and thereby reduced DA uptake functionality until all surface DATs were inactivated. DATs that were not cross-linked by CuP showed normal DA uptake with DA Km at ~ 0.5 μM and DA efflux with basal and amphetamine-induced DA efflux as much as control values. The cocaine analog 2β-carbomethoxy-3β-[4-fluorophenyl]-tropane (CFT) was capable to bind to copper-cross-linked DATs, albeit with an affinity more than 5 fold decreased (Kd of CFT =109 nM after crosslinking vs 19 nM before). A kinetic analysis is offered describing the changing amounts of dimers and monomers with increasing [CuP], allowing the estimation of dimer functional activity compared with a DAT monomer. Consonant with previous conclusions for SERT and NET that only one protomer of an oligomer is active at the time, the present data indicated -a functional activity of the DAT dimer of 0.74 relative to a monomer. This article is protected by copyright. All rights reserved.
Datum: 23.11.2017


New tool to tackle Alzheimer's disease: amyloid-β protofibril-selective antibody AbSL

This Editorial highlights a study by Colvin et al. (2017) in the current issue of Journal of Neurochemistry, in which the authors describe the development and characterisation of a new rabbit antibody (termed antibody St. Louis; AbSL) that preferentially recognises amyloid-β (Aβ) protein 42 (Aβ42) protofibrils over other Aβ species.
Datum: 23.11.2017


The conformational epitope for a new Aβ42 protofibril-selective antibody partially overlaps with the peptide N-terminal region

Aggregation and accumulation of amyloid-β peptide (Aβ) is a key component of Alzheimer's disease (AD). While monomeric Aβ appears to be benign, oligomers adopt a biologically detrimental structure. These soluble structures can be detected in AD brain tissue by antibodies that demonstrate selectivity for aggregated Aβ. Protofibrils are a subset of soluble oligomeric Aβ species and are described as small (< 100 nm) curvilinear assemblies enriched in β-sheet structure. Our own in vitro studies demonstrate that microglial cells are much more sensitive to soluble Aβ42 protofibrils compared to Aβ42 monomer or insoluble Aβ42 fibrils. Protofibrils interact with microglia, trigger Toll-like receptor signaling, elicit cytokine transcription and expression, and are rapidly taken up by the cells. Because of the importance of this Aβ species, we sought to develop an antibody that selectively recognizes protofibrils over other Aβ species. Immunization of rabbits with isolated Aβ42 protofibrils generated a high-titer anti serum with a strong affinity for Aβ42 protofibrils. The antiserum, termed AbSL, was selective for Aβ42 protofibrils over Aβ42 monomers and Aβ42 fibrils. AbSL did not react with amyloid precursor protein and recognized distinct pathological features in AD transgenic mouse brain slices. Competition studies with an Aβ antibody that targets residues 1–16 indicated that the conformational epitope for AbSL involved the N-terminal region of protofibrils in some manner. The newly developed antibody may have potential diagnostic and therapeutic uses in AD tissue and patients, and targeting of protofibrils in AD may have beneficial effects. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14240. Aggregation and accumulation of amyloid-β peptide (Aβ) is a key component of Alzheimer's disease (AD). The aggregation process yields a variety of soluble (protofibrils) and insoluble (fibrils) species. Because of the importance of protofibrils, an antiserum, termed AbSL, was developed and found to be selective for Aβ protofibrils over monomers and fibrils. The newly developed antibody may have potential diagnostic and therapeutic uses. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14240.
Datum: 22.11.2017


Repair gene MGMT is controlled by SP1 and upregulated by glucocorticoids, but not by temozolomide and radiation

Therapy of malignant glioma relies on treatment with the O6-methylating agent temozolomide (TMZ) concomitant with ionizing radiation followed by adjuvant TMZ. For the treatment of recurrences DNA chloroethylating drugs are also used. The main killing lesion induced by these drugs is O6-alkylguanine. Since this damage is repaired by O6-methylguanine-DNA methyltransferase (MGMT), the repair enzyme represents the most important factor of drug resistance, limiting the therapy of malignant high-grade gliomas. Whereas MGMT has been shown to be transcriptionally upregulated in rodents following genotoxic stress, it is still unclear whether human MGMT is subject to upregulation. Here, we addressed the question whether MGMT in glioma cells is enhanced following alkylating drugs or ionizing radiation, using promoter assays. We also checked the response of glioma cell lines to dexamethasone. In a series experiments we found no evidence that the human MGMT promoter is significantly upregulated following treatment with TMZ, the chloroethylating agent nimustine (ACNU) or radiation. It was activated however by dexamethasone. Using deletion constructs, we further show that the basal level of MGMT is mainly determined by the transcription factor SP1. The high amount of SP1 sites in the MGMT promoter likely prevents transcriptional upregulation following genotoxic stress by neutralizing inducible signals. The regulation of MGMT by miRNAs plays only a minor role, as shown by DICER knockdown experiments. Since high dose dexamethasone concomitant with temozolomide is frequently used in glioblastoma therapy, induction of the MGMT gene through glucocorticoids in MGMT promoter unmethylated cases might cause further elevation of drug resistance, while radiation and alkylating drugs seem not to induce MGMT at the transcriptional level. This article is protected by copyright. All rights reserved.
Datum: 22.11.2017


Calmodulin-like skin protein protects against spatial learning impairment in a mouse model of Alzheimer disease

Humanin and calmodulin-like skin protein (CLSP) inhibits Alzheimer disease (AD)-related neuronal cell death via the heterotrimeric humanin receptor in vitro. It has been suggested that CLSP is a central agonist of the heterotrimeric humanin receptor in vivo. To investigate the role of CLSP in the AD pathogenesis in vivo, we generated mouse CLSP-1 transgenic mice, crossed them with the APPswe/PSEN1dE9 mice, a model mouse of AD, and examined the effect of CLSP overexpression on the pathological phenotype of the AD mouse model. We found that overexpression of the mouse CLSP-1 gene attenuated spatial learning impairment, the loss of a presynaptic marker synaptophysin, and the inactivation of STAT3 in the APPswe/PSEN1dE9 mice. On the other hand, CLSP overexpression did not affect levels of Aβ, soluble Aβ oligomers, or gliosis. These results suggest that the CLSP-mediated attenuation of memory impairment and synaptic loss occurs in an Aβ-independent manner. The results of the current study may serve as a hint to the better understanding of the AD pathogenesis and the development of AD therapy. This article is protected by copyright. All rights reserved.
Datum: 22.11.2017


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 (EAAT3) in retinal neuronal cultures. Interestingly, vitamin C is prone to increase the activity of NMDA receptors but also promotes a decrease of 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 (CREB) 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. This article is protected by copyright. All rights reserved.
Datum: 22.11.2017


Protection Against β-Amyloid Neurotoxicity by a Non-Toxic Endogenous N-terminal β-Amyloid Fragment and its Active Hexapeptide Core Sequence

High levels (μM) of beta amyloid (Aβ) oligomers are known to trigger neurotoxic effects, leading to synaptic impairment, behavioral deficits and apoptotic cell death. The hydrophobic C-terminal domain of Aβ, together with sequences critical for oligomer formation, is essential for this neurotoxicity. However, Aβ at low levels (pM-nM) has been shown to function as a positive neuromodulator and this activity resides in the hydrophilic N-terminal domain of Aβ. An N-terminal Aβ fragment (1-15/16), found in cerebrospinal fluid, was also shown to be a highly active neuromodulator and to reverse Aβ-induced impairments of long-term potentiation. Here, we show the impact of this N-terminal Aβ fragment and a shorter hexapeptide core sequence in the Aβ fragment (Aβcore: 10-15) to protect or reverse Aβ-induced neuronal toxicity, fear memory deficits and apoptotic death. The neuroprotective effects of the N-terminal Aβ fragment and Aβcore on Aβ-induced changes in mitochondrial function, oxidative stress and apoptotic neuronal death were demonstrated via mitochondrial membrane potential, live reactive oxygen species, DNA fragmentation and cell survival assays using a model neuroblastoma cell line (differentiated NG108-15) and mouse hippocampal neuron cultures. The protective action of the N-terminal Aβ fragment and Aβcore against spatial memory processing deficits in APP/PSEN1 (5XFAD) mice was demonstrated in contextual fear conditioning. Stabilized derivatives of the N-terminal Aβcore were also shown to be fully protective against Aβ-triggered oxidative stress. Together, these findings indicate an endogenous neuroprotective role for the N-terminal Aβ fragment, while active stabilized N-terminal Aβcore derivatives offer the potential for therapeutic application. This article is protected by copyright. All rights reserved.
Datum: 22.11.2017


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 due to 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. This article is protected by copyright. All rights reserved.
Datum: 22.11.2017


Epigenetic control of early neurodegenerative events in diabetic retinopathy by the histone deacetylase SIRT6

Diabetic retinopathy (DR) is one of the common complications associated with diabetes mellitus and the leading cause of blindness worldwide. Recent research has demonstrated that DR is not only a microvascular disease but may be a result of neurodegenerative processes. Moreover, glucose-induced neuron and glial cell damage may occur shortly after the onset of diabetes which makes the disease hard to diagnose at early stages. SIRT6, a NAD-dependent sirtuin deacylase, modulates aging, energy metabolism, and neurodegeneration. In previous studies we showed that SIRT6 deficiency causes major retinal transmission defects, changes in the expression of glycolytic genes, and elevated levels of apoptosis. Given the importance of glucose availability for retinal function and the critical role of SIRT6 in modulating glycolysis, we aimed to analyze SIRT6 participation in the molecular machinery that regulates the development of experimental DR. Using non-obese diabetic mice, we determined by western blot that 2 weeks after the onset of the disease, high glucose concentrations induced retinal increase in a neovascularization promoting factor (vascular endothelial growth factor, VEGF), and the loss of a neuroprotective factor (brain-derived neurotrophic factor, BDNF) associated with reduced levels of SIRT6 and increased acetylation levels of its substrates (H3K9 and H3K56) suggesting a deregulation of key neural factors. Noteworthy, retinas from CNS conditionally deleted SIRT6 mice showed a resemblance to diabetic retinas exhibiting lower protein levels of BDNF factor and increased protein levels of VEGF. Moreover, cultured Müller glial cells subjected to high glucose concentrations exhibited decreased levels of SIRT6 and increased levels of H3K56 acetylation. In addition, the increment of VEGF levels induced by high glucose was reverted by the over-expression of SIRT6 in this cell type. Accordingly, siRNA experiments showed that, when SIRT6 was silenced, VEGF levels increased. Our findings suggest that epigenetically regulated neurodegenerative events may occur at an early diabetic stage prior to the characteristic proliferative and vascular changes observed at a later diabetic stage. Diabetic Retinopathy is not only a microvascular disease but a result of neurodegenerative processes. SIRT6 is a NAD-dependent histone deacetylase that modulates glucose metabolism and neurodegeneration. We demonstrated that high glucose concentrations induced a reduction in retinal SIRT6 levels associated with increased acetylation levels of its substrates (H3K9 and H3K56) that in turn promotes an increase in the vascular endothelial growth factor (VEGF) and a decrease in the brain-derived neurotrophic factor (BDNF) suggesting that epigenetically regulated neurodegenerative events may occur prior to the vascular changes observed at a later diabetic stage.
Datum: 21.11.2017


Ca2+-dependent down-regulation of human histamine H1 receptors in Chinese hamster ovary cells

Gq/11 protein-coupled human histamine H1 receptors in Chinese hamster ovary cells stimulated with histamine undergo clathrin-dependent endocytosis followed by proteasome/lysosome-mediated down-regulation. In this study, we evaluated the effects of a sustained increase in intracellular Ca2+ concentrations induced by a receptor-bypassed stimulation with ionomycin, a Ca2+ ionophore, on the endocytosis and down-regulation of H1 receptors in Chinese hamster ovary cells. All cellular and cell-surface H1 receptors were detected by the binding of [3H]mepyramine to intact cells sensitive to the hydrophobic and hydrophilic H1 receptor ligands, mepyramine and pirdonium, respectively. The pretreatment of cells with ionomycin markedly reduced the mepyramine- and pirdonium-sensitive binding sites of [3H]mepyramine, which were completely abrogated by the deprivation of extracellular Ca2+ and partially by a ubiquitin-activating enzyme inhibitor (UBEI-41), but were not affected by inhibitors of calmodulin (W-7 or calmidazolium) and protein kinase C (chelerythrine or GF109203X). These ionomycin-induced changes were also not affected by inhibitors of receptor endocytosis via clathrin (hypertonic sucrose) and caveolae/lipid rafts (filipin or nystatin) or by inhibitors of lysosomes (E-64, leupeptin, chloroquine, or NH4Cl), proteasomes (lactacystin or MG-132), and a Ca2+-dependent non-lysosomal cysteine protease (calpain) (MDL28170). Since H1 receptors were normally detected by confocal immunofluorescence microscopy with an antibody against H1 receptors, even after the ionomycin treatment, H1 receptors appeared to exist in a form to which [3H]mepyramine was unable to bind. These results suggest that H1 receptors are apparently down-regulated by a sustained increase in intracellular Ca2+ concentrations with no process of endocytosis and lysosomal/proteasomal degradation of receptors. We investigated effects of receptor-bypassed increases in intracellular Ca2+ concentrations with a Ca2+ ionophore, ionomycin, on the number of human histamine H1 receptors in CHO cells. Ionomycin induced down-regulation of H1 receptors via Ca2+-dependent but calmodulin/protein kinase C/calpain-independent mechanisms with no apparent endocytosis and lysosomal/proteasomal degradation of receptors in a manner different from those induced by receptor agonist.
Datum: 21.11.2017


Endogenous ghrelin-O-acyltransferase (GOAT) acylates local ghrelin in the hippocampus

Ghrelin is an appetite-stimulating peptide. Serine 3 on ghrelin must be acylated by octanoate via the enzyme ghrelin-O-acyltransferase (GOAT) for the peptide to bind and activate the cognate receptor, growth hormone secretagogue receptor type 1a (GHSR1a). Interest in GHSR1a increased dramatically when GHSR1a mRNA was demonstrated to be widespread in the brain, including the cortex and hippocampus, indicating that it has multifaceted functions beyond the regulation of metabolism. However, the source of octanoylated ghrelin for GHSR1a in the brain, outside of the hypothalamus, is not well understood. Here, we report the presence of GOAT and its ability to acylate non-octanoylated ghrelin in the hippocampus. GOAT immunoreactivity is aggregated at the base of the dentate granule cell layer in the rat and wild-type mouse. This immunoreactivity was not affected by the pharmacological inhibition of GHSR1a or the metabolic state-dependent fluctuation of systemic ghrelin levels. However, it was absent in the GHSR1a knockout mouse hippocampus, pointing the possibility that the expression of GHSR1a may be a prerequisite for the production of GOAT. Application of fluorescein isothiocyanate (FITC)-conjugated non-octanoylated ghrelin in live hippocampal slice culture (but not in fixed culture or in the presence of GOAT inhibitors) mimicked the binding profile of FITC-conjugated octanoylated ghrelin, suggesting that extracellularly applied non-octanoylated ghrelin was acylated by endogenous GOAT in the live hippocampus while GOAT being mobilized out of neurons. Our results will advance the understanding for the role of endogenous GOAT in the hippocampus and facilitate the search for the source of ghrelin that is intrinsic to the brain. To elucidate a cellular mechanism for the ghrelin-mediated regulation of hippocampal function, we demonstrate that endogenous ghrelin-O-acyltransferase (GOAT) is present in the dentate gyrus of the hippocampus and biologically active to acylate local des-acyl ghrelin. Failure of detecting GOAT immunoreactive products in the growth hormone secretagogue receptor type 1a (GHSR1a) KO mouse hippocampus suggests that the expression of GHSR1a is likely a prerequisite for GOAT production in the hippocampus.
Datum: 20.11.2017


Nutrient-driven O-GlcNAc in proteostasis and neurodegeneration

Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient-sensitive nucleocytoplasmic post-translational modification O-linked N-acetylglucosamine (O-GlcNAc) regulates protein homeostasis. The O-GlcNAc modification is highly abundant in the mammalian brain and has been linked to proteopathies, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. C. elegans, Drosophila, and mouse models harboring O-GlcNAc transferase- and O-GlcNAcase-knockout alleles have helped define the role O-GlcNAc plays in development as well as age-associated neurodegenerative disease. These enzymes add and remove the single monosaccharide from protein serine and threonine residues, respectively. Blocking O-GlcNAc cycling is detrimental to mammalian brain development and interferes with neurogenesis, neural migration, and proteostasis. Findings in C. elegans and Drosophila model systems indicate that the dynamic turnover of O-GlcNAc is critical for maintaining levels of key transcriptional regulators responsible for neurodevelopment cell fate decisions. In addition, pathways of autophagy and proteasomal degradation depend on a transcriptional network that is also reliant on O-GlcNAc cycling. Like the quality control system in the endoplasmic reticulum which uses a ‘mannose timer’ to monitor protein folding, we propose that cytoplasmic proteostasis relies on an ‘O-GlcNAc timer’ to help regulate the lifetime and fate of nuclear and cytoplasmic proteins. O-GlcNAc-dependent developmental alterations impact metabolism and growth of the developing mouse embryo and persist into adulthood. Brain-selective knockout mouse models will be an important tool for understanding the role of O-GlcNAc in the physiology of the brain and its susceptibility to neurodegenerative injury. Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient-sensitive nucleocytoplasmic post-translational modification O-linked N-acetylglucosamine (O-GlcNAc) regulates protein homeostasis. This cyclic modification is coordinately regulated with other PTMs such as phosphorylation to regulate the required intricacies of cellular processes. Deregulation of PTMs including O-GlcNAc leads to several pathologies that are associated with neurodegeneration.
Datum: 20.11.2017


Adropin preserves the blood-brain barrier through a Notch1/Hes1 pathway after intracerebral hemorrhage in mice

Adropin is expressed in the CNS and plays a crucial role in the development of stroke. However, little is currently known about the effects of adropin on the blood-brain barrier (BBB) function after intracerebral hemorrhage (ICH). In this study, the role of adropin in collagenase-induced ICH was investigated in mice. At 1-h post-ICH, mice were administered with recombinant human adropin by intranasal. Brain water +content, BBB permeability, and neurological function were measured at different time intervals. Proteins were quantified using western blot analysis, and the localizations of adropin and Notch1 were visualized via immunofluorescence staining. It is shown that adropin reduced brain water content and improved neurological functions. Adropin preserved the functionality of BBB by increasing N-cadherin expression and reducing extravasation of albumin. Moreover, in vivo knockdown of Notch1 and Hes1 both abolished the protective effects of adropin. Taken together, our data demonstrate that adropin constitutes a potential treatment value for ICH by preserving BBB and improving functional outcomes through the Notch1 signaling pathway. Adropin is expressed in the central nervous system (CNS) and plays a crucial role in the development of stroke. In this study, the role of adropin in collagenase-induced ICH was investigated in mice. Our research demonstrates that adropin constitutes a potential treatment value for ICH by preserving BBB and improving functional outcomes through the Notch1 signaling pathway.
Datum: 17.11.2017


Issue Information


Datum: 17.11.2017


Issue Cover (December 2017)

Front cover: Co-culturing astrocytes (GFAP, green) with endothelial cells (CD31, yellow) increases cleaved Notch1 (NICD, red) in astrocytic nuclei and induces expression of the glial glutamate transporter GLT-1. These results suggest a novel role for endothelial cells in the regulation of astrocytic function via a Notch-dependent mechanism. Read the full article ‘Brain endothelial cells induce astrocytic expression of the glutamate transporter GLT-1 by a Notch-dependent mechanism’ by M. L. Lee, Z. Martinez-Lozada, E. N. Krizman and M. B. Robinson (J. Neurochem. 2017, vol. 143(5), pp. 489–506) on doi: 10.1111/jnc.14135
Datum: 17.11.2017


Fisetin provides antidepressant effects by activating the tropomyosin receptor kinase B signal pathway in mice

Depression has been associated with a low-grade chronic inflammatory state, suggesting a potential therapeutic role for anti-inflammatory agents. Fisetin is a naturally occurring flavonoid in strawberries that has anti-inflammatory activities, but whether fisetin has antidepressant effects is unknown. In this study, we exposed mice to spatial restraint for 2 weeks with or without treatment with fisetin. Immobility time in the forced swimming and tail suspension test after this restraint increased in the untreated group, but this increase did not occur in the fisetin group. We administered fisetin to Abelson helper integration site-1 (Ahi1) knockout mice, which have depressive phenotypes. We found that fisetin attenuated the depressive phenotype of these Ahi1 knockout mice. We further investigated the potential mechanism of fisetin's antidepressant effects. Because TrkB is a critical signaling pathway in the mechanisms of depression, we examined whether phosphorylated TrkB was involved in the antidepressant effects of fisetin. We found that fisetin increased phosphorylated TrkB level without altering total TrkB; this increase was attenuated by K252a, a specific TrkB inhibitor. Taken together, our results demonstrated that fisetin may have therapeutic potential for treating depression and that this antidepressant effect may be mediated by the activation of the TrkB signaling pathway. Depression is one of the leading causes of morbidity and mortality worldwide. Because of the substantial side effects of many antidepressants, there is an urgent need to find safer and effective therapeutic agents. In this study, we demonstrate that fisetin, a naturally occurring flavonoid, has therapeutic potential for major depression and its antidepressant effect is mediated by activating the TrkB signaling pathway.
Datum: 17.11.2017


Protein components of postsynaptic density lattice, a backbone structure for type I excitatory synapses

It is essential to study the molecular architecture of postsynaptic 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, are 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, while 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. Based on 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 sub-domain 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. This article is protected by copyright. All rights reserved.
Datum: 14.11.2017


Mechanistic contributions of FBXO7 to Parkinson's disease

Parkinson's disease (PD) is, without doubt, a burden on modern society as the prevalence increases significantly with age. Owing to this growing number of PD cases, it is more critical than ever to understand the pathogenic mechanisms underlying PD to identify therapeutic targets. The discovery of genetic mutations associated with PD and parkinsonism paves the way toward this goal. Even though, familial forms of the disease represent the minority of PD cases and some forms are so rare that there are only a few affected families, the research on the associated genes is invaluable. Recent additions to PARK mutations are those in PARK15 that encodes the F-box protein FBXO7. In this review, we highlight the recent research on FBXO7, which advances our knowledge of the etiopathological pathways and fills unexpected gaps therein, justifying the dedicated study of rare variants of PD. This article is protected by copyright. All rights reserved.
Datum: 14.11.2017


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, a need exists to find new ways of investigating 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 12m-old 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 18m-old TG mice when compared to age matched WT mice and 6m-old TG mice. No overall effect of gene was seen on metabolite levels; however a significant reduction in NAA was observed in 18m-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 aging.
Datum: 10.11.2017


Astrocytes with previous chronic exposure to amyloid β-peptide fragment 1–40 suppress excitatory synaptic transmission

Synaptic dysfunction and neuronal death are responsible for cognitive and behavioral deficits in Alzheimer's disease (AD). It is well known that such neurological abnormalities are preceded by long-term exposure of amyloid β-peptide (Aβ) and/or hyperphosphorylated tau prior. In addition to the neurological deficit, astrocytes as a major glial cell type in the brain, significantly participate in the neuropathogenic mechanisms underlying synaptic modulation. Although astrocytes play a significant key role in modulating synaptic transmission, little is known on whether astrocyte dysfunction caused by such long-term Aβ exposure affects synapse formation and function. Here, we show that synapse formation and synaptic transmission are attenuated in hippocampal-naïve neurons co-cultured with astrocytes that have previously experienced chronic Aβ1-40 exposure. In this abnormal astrocytic condition, hippocampal neurons exhibit decrements of evoked excitatory post-synaptic currents (EPSCs) and miniature EPSC frequency. Furthermore, size of readily releasable synaptic pools and number of excitatory synapses were also significantly decreased. Contrary to these negative effects, release probability at individual synapses was significantly increased in the same astrocytic condition. Taken together, our data indicate that lower synaptic transmission caused by astrocytes previously, and chronically, exposed to Aβ1–40 is attributable to a small number of synapses with higher release probability. Astrocytes are the major glial cell type of the brain, and among their many roles are involved in amyloid β (Aβ) clearance and synapse function. Aβ1-40-exposed astrocytes lead to reduced glutamatergic synaptic transmission, but enhanced synapse function at the individual level. This suggests that astrocytic pathological changes induced by long-term Aβ1-40 treatment may adversely affect neurotransmission in AD brain.
Datum: 10.11.2017


16p11.2 deletion syndrome mice perseverate with active coping response to acute stress – rescue by blocking 5-HT2A receptors

In humans a chromosomal hemideletion of the 16p11.2 region results in variable neurodevelopmental deficits including developmental delay, intellectual disability, and features of autism spectrum disorder (ASD). Serotonin is implicated in ASD but its role remains enigmatic. In this study we sought to determine if and how abnormalities in serotonin neurotransmission could contribute to the behavioral phenotype of the 16p11.2 deletion syndrome in a mouse model (Del mouse). As ASD is frequently associated with altered response to acute stress and stress may exacerbate repetitive behavior in ASD, we studied the Del mouse behavior in the context of an acute stress using the forced swim test, a paradigm well characterized with respect to serotonin. Del mice perseverated with active coping (swimming) in the forced swim test and failed to adopt passive coping strategies with time as did their wild-type littermates. Analysis of monoamine content by HPLC provided evidence for altered endogenous serotonin neurotransmission in Del mice while there was no effect of genotype on any other monoamine. Moreover, we found that Del mice were highly sensitive to the 5-HT2A antagonists M100907, which at a dose of 0.1 mg/kg normalized their level of active coping and restored the gradual shift to passive coping in the forced swim test. Supporting evidence for altered endogenous serotonin signaling was provided by observations of additional ligand effects including altered forebrain Fos expression. Taken together, these observations indicate notable changes in endogenous serotonin signaling in 16p11.2 deletion mice and support the therapeutic utility of 5-HT2A receptor antagonists. In humans a chromosomal hemideletion of the 16p11.2 region results in variable neurodevelopmental deficits including developmental delay, intellectual disability, and features of autism spectrum disorder (ASD). Mice modeling this human chromosomal hemideletion of the 16p11.2 region show robust perseverative active coping in response to acute stress (swim). This phenotype is completely normalized by a 5-HT2A-receptor antagonist. These results indicate a strong potential for the therapeutic utility of 5-HT2A antagonists and also illustrate the utility of studying autism-relevant mouse models in the context of stress.
Datum: 10.11.2017


Lateral hypothalamic Orexin-A-ergic projections to the arcuate nucleus modulate gastric function in vivo

It has been well-known that hypothalamic orexigenic neuropeptides, orexin-A, and melanin-concentrating hormone (MCH), play important roles in regulation of gastric function. However, what neural pathway mediated by the two neuropeptides affects the gastric function remains unknown. In this study, by way of nucleic stimulation and extracellular recording of single unit electrophysiological properties, we found that electrically stimulating the lateral hypothalamic area (LH) or microinjection of orexin-A into the arcuate nucleus (ARC) excited most gastric distension-responsive neurons in the nuclei and enhanced the gastric function including motility, emptying, and acid secretion of conscious rats. The results indicated that LH-ARC orexin-A-ergic projections may exist and the orexin-A in the ARC affected afferent and efferent signal transmission between ARC and stomach. As expected, combination of retrograde tracing and immunohistochemistry showed that some orexin-A-ergic neurons projected from the LH to the ARC. In addition, microinjection of MCH and its receptor antagonist PMC-3881-PI into the ARC affected the role of orexin-A in the ARC, indicating a possible involvement of the MCH pathway in the orexin-A role. Our findings suggest that there was an orexin-A-ergic pathway between LH and ARC which participated in transmitting information between the central nuclei and the gastrointestinal tract and in regulating the gastric function of rats. This study aimed to reveal whether and how the hypothalamic orexin-A and melanin-concentrating hormone (MCH) participated in the regulation of gastric function. We found that orexin-A, when microinjected into the arcuate nucleus (ARC), regulated the gastric distension (GD)-responsive neurons and enhanced gastric motility, which were partly blocked by SB334867 or PMC-3881-PI, antagonists for orexin-A receptor and MCH receptor, respectively. The latter indicated that MCH pathway was likely involved in the process. Electrical stimulation of the lateral hypothalamic area (LH) increased the firing activities of GD-responsive neurons in the ARC and promoted the gastric motility. When fluorogold was injected to the ARC, orexin-A/fluorogold double-labeled neurons were identified in the LH, indicating that HL-ARC orexin-A-ergic projections existed, orexin-A in the LH played a pivotal role in the central regulation of gastric motility and the ARC participated in the regulatory process of LH.
Datum: 07.11.2017


Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies

Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty-four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations. Hereditary neuropathies are chronic, disabling diseases subclassified by different pheno- and genotypes. Using a next generation sequencing-based (NGS) panel, we identified putative causative mutations in 121 of 612 cases. We discussed the pathogenicity of 34 novel variants and characterized four exemplary patient histories concluding that NGS-based panels are a time- and cost-effective tool to enable an appropriate diagnosis.
Datum: 07.11.2017


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


Negative modulation of the GABAAρ1 receptor function by l-cysteine

l-Cysteine is an endogenous sulfur-containing amino acid with multiple and varied roles in the central nervous system, including neuroprotection and the maintenance of the redox balance. However, it was also suggested as an excitotoxic agent implicated in the pathogenesis of neurological disorders such as Parkinson′s and Alzheimer′s disease. l-Cysteine can modulate the activity of ionic channels, including voltage-gated calcium channels and glutamatergic NMDA receptors, whereas its effects on GABAergic neurotransmission had not been studied before. In the present work, we analyzed the effects of l-cysteine on responses mediated by homomeric GABAAρ1 receptors, which are known for mediating tonic γ-aminobutyric acid (GABA) responses in retinal neurons. GABAAρ1 receptors were expressed in Xenopus laevis oocytes and GABA-evoked chloride currents recorded by two-electrode voltage-clamp in the presence or absence of l-cysteine. l-Cysteine antagonized GABAAρ1 receptor-mediated responses; inhibition was dose-dependent, reversible, voltage independent, and susceptible to GABA concentration. Concentration-response curves for GABA were shifted to the right in the presence of l-cysteine without a substantial change in the maximal response. l-Cysteine inhibition was insensitive to chemical protection of the sulfhydryl groups of the ρ1 subunits by the irreversible alkylating agent N-ethyl maleimide. Our results suggest that redox modulation is not involved during l-cysteine actions and that l-cysteine might be acting as a competitive antagonist of the GABAAρ1 receptors. l-Cysteine (l-Cys) is an endogenous sulfur containing amino acid with multiple roles in the central nervous system. In this work we report the modulation of homomeric GABAAρ1 receptors by l-Cys. l-Cys inhibited GABAAρ1 receptor-mediated responses in a dose-dependent and reversible manner. Experimental data indicate that l-Cys acts as a competitive antagonist. Receptor scheme shows one of the binding sites (out of five) for GABA, which eventually mediates l-Cys effects.
Datum: 07.11.2017


Impaired AMPA receptor trafficking by a double knockout of zebrafish olfactomedin1a/b

The olfm1a and olfm1b genes in zebrafish encode conserved secreted glycoproteins. These genes are preferentially expressed in the brain and retina starting from 16 h post-fertilization until adulthood. Functions of the Olfm1 gene is still unclear. Here, we produced and analyzed a null zebrafish mutant of both olfm1a and olfm1b genes (olfm1 null). olfm1 null fish were born at a normal Mendelian ratio and showed normal body shape and fertility as well as no visible defects from larval stages to adult. Olfm1 proteins were preferentially localized in the synaptosomes of the adult brain. Olfm1 co-immunoprecipitated with GluR2 and soluble NSF attachment protein receptor complexes indicating participation of Olfm1 in both pre- and post-synaptic events. Phosphorylation of GluR2 was not changed while palmitoylation of GluR2 was decreased in the brain synaptosomal membrane fraction of olfm1 null compared with wt fish. The levels of GluR2, SNAP25, flotillin1, and VAMP2 were markedly reduced in the synaptic microdomain of olfm1 null brain compared with wt. The internalization of GluR2 in retinal cells and the localization of VAMP2 in brain synaptosome were modified by olfm1 null mutation. This indicates that Olfm1 may regulate receptor trafficking from the intracellular compartments to the synaptic membrane microdomain, partly through the alteration of post-translational GluR2 modifications such as palmitoylation. Olfm1 may be considered a novel regulator of the composition and function of the α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor complex. Olfactomedin 1 (Olfm1) is known to interact with the AMPA receptor complex. This study shows that Olfm1 is preferentially localized in the synaptosomes of the adult brain. Olfm1 may regulate receptor trafficking from the intracellular compartments to the synaptic membrane microdomain, partly through the alteration of post-translational GluR2 modifications such as palmitoylation. Olfm1 may be considered a novel regulator of the composition and function of the AMPAR complex.
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


Reduced Blood-Brain Barrier Expression of Fatty-Acid Binding Protein 5 is associated with Increased Vulnerability of APP/PS1 mice to Cognitive Deficits from Low Omega-3 Fatty Acid Diets

Lower levels of the cognitively-beneficial docosahexaenoic acid (DHA) are often observed in Alzheimer's disease (AD) brains. Brain DHA levels are regulated by the blood-brain barrier (BBB) transport of plasma-derived DHA, a process facilitated by fatty acid-binding protein 5 (FABP5). This study reports a 42.1 ± 12.6% decrease in the BBB transport of 14C-DHA in 8-month AD transgenic mice (APPswe,PSEN1∆E9) relative to wild-type, associated with a 34.5 ± 6.7% reduction in FABP5 expression in isolated brain capillaries of AD mice. Furthermore, short-term spatial and recognition memory deficits were observed in AD mice on a 6-month n-3 fatty acid-depleted diet, but not in AD mice on control diet. This intervention led to a dramatic reduction (41.5 ± 11.9%) of brain DHA levels in AD mice. This study demonstrates FABP5 deficiency and impaired DHA transport at the BBB, which are associated with increased vulnerability to cognitive deficits in mice fed an n-3 fatty acid-depleted diet, in line with our previous studies demonstrating a crucial role of FABP5 in BBB transport of DHA and cognitive function. This article is protected by copyright. All rights reserved.
Datum: 03.11.2017


Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis

Glutathione (GSH) and GSH-related enzymes constitute the most important defense system that protects cells from free radical, radiotherapy, and chemotherapy attacks. In this study, we aim to explore the potential role and regulatory mechanism of the GSH redox cycle in drug resistance in glioblastoma multiforme (GBM) cells. We found that temozolomide (TMZ)-resistant glioma cells displayed lower levels of endogenous ROS and higher levels of total antioxidant capacity and GSH than sensitive cells. Moreover, the expression of glutathione reductase (GSR), the key enzyme of the GSH redox cycle, was higher in TMZ-resistant cells than in sensitive cells. Furthermore, silencing GSR in drug-resistant cells improved the sensitivity of cells to TMZ or cisplatin. Conversely, the overexpression of GSR in sensitive cells resulted in resistance to chemotherapy. In addition, the GSR enzyme partially prevented the oxidative stress caused by pro-oxidant L-buthionine -sulfoximine (BSO). The modulation of redox state by GSH or BSO regulated GSR-mediated drug resistance, suggesting that the action of GSR in drug resistance is associated with the modulation of redox homeostasis. Intriguingly, a trend towards shorter progress-free survival was observed among GBM patients with high GSR expression. These results indicated that GSR is involved in mediating drug resistance and is a potential target for improving GBM treatment. This article is protected by copyright. All rights reserved.
Datum: 03.11.2017


Clenbuterol reduces GABAergic transmission prefrontal cortex layer 5/6 pyramidal neurons of juvenile rat via reducing action potentials firing frequency of GABAergic interneurons

β2-adrenoceptors (β2-ARs) have beneficial effects on prefrontal cortex (PFC) working memory, however, the cellular and molecular mechanisms are unclear yet. In the current study, we probed the effect of β2-AR selective agonist Clenbuterol (Clen) on synaptic transmission in layer 5/6 pyramidal neurons of PFC. Bath application of Clen reduced spontaneous IPSC (sIPSC) frequency without effects on sEPSCs. Clen did not alter the frequency and amplitude of miniature IPSCs (mIPSCs), but exerted heterogeneous effects on evoked IPSCs (eIPSCs) recorded from PFC layer 5/6 pyramidal neurons. Clen decreased the firing rate of action potentials of fast-spiking GABAergic interneurons. Clen-induced hyperpolarization of fast-spiking GABAergic interneurons required potentiation of an inward rectifier K+ channels (Kirs). Clen-induced hyperpolarization of fast-spiking interneurons was dependent on Gs protein rather than cAMP and protein kinase A (PKA). Our findings demonstrate that Clen (10 μM) enhances Kirs via Gs protein to cause membrane hyperpolarization of fast-spiking GABAergic interneurons resulting in reduction of action potentials firing rate to reduce GABAergic transmission. This article is protected by copyright. All rights reserved.
Datum: 31.10.2017


DJ-1 deficiency impairs autophagy and reduces alpha-synuclein phagocytosis by microglia

Parkinson's disease (PD) is a progressive neurodegenerative disorder, of which 1% of the hereditary cases are linked to mutations in DJ-1, an oxidative stress sensor. The pathological hallmark of PD is intercellular inclusions termed Lewy Bodies, composed mainly of α-Synuclein (α-Syn) protein. Recent findings have shown that α-Syn can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing α-Syn. We previously reported that the knock down (KD) of DJ-1 in microglia increased cells’ neurotoxicity to dopaminergic neurons. Here, we discovered that α-Syn significantly induced elevated secretion of the proinflammatory cytokines IL-6 and IL-1β and a significant dose-dependent elevation in the production of nitric oxide in DJ-1 KD microglia, compared to control microglia. We further investigated the ability of DJ-1 KD microglia to uptake and degrade soluble α-Syn, and discovered that DJ-1 KD reduces cell-surface lipid raft expression in microglia and impairs their ability to uptake soluble α-Syn. Autophagy is an important mechanism for degradation of intracellular proteins and organelles. We discovered that DJ-1 KD microglia exhibit an impaired autophagy-dependent degradation of p62 and LC3 proteins, and that manipulation of autophagy had less effect on α-Syn uptake and clearance in DJ-1 KD microglia, compared to control microglia. Further studies of the link between DJ-1, α-Syn uptake and autophagy may provide useful insights into the role of microglia in the etiology of the PD. One percent of the hereditary cases of Parkinson's disease are linked to mutations in DJ-1, an oxidative stress sensor. Recent findings have shown that alpha-synuclein (α-Syn) can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing α-Syn. Our paper suggests that DJ-1 deficiency alters the response of microglia toward αSyn. We found that DJ-1 deficient microglia exhibit increased inflammatory responses toward αSyn as shown by elevated secretion of the proinflammatory cytokines IL-6 and IL-1β. Furthermore, DJ-1-deficient microglia have specific impairments in the uptake and degradation of soluble α-Syn, which may be linked, respectively, to their reduction in cell-surface lipid raft expression and impaired autophagy, an important mechanism for degradation of intracellular protein aggregates and damaged organelles (green: autophagosome, red: lysosome, green+red: autophagolysosome).
Datum: 30.10.2017


Activation of the NLRP3 inflammasome in microglia: the role of ceramide

Inflammation within the CNS is a major component of many neurodegenerative diseases. A characteristic feature is the generation of microglia-derived factors that play an essential role in the immune response. IL-1β is a pro-inflammatory cytokine released by activated microglia, able to exacerbate injury at elevated levels. In the presence of caspase-1, pro-IL-1β is cleaved to the mature cytokine following NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation. Growing evidence suggests that ceramide plays a critical role in NLRP3 inflammasome assembly, however, the relationship between ceramide and inflammasome activation in microglia remains unknown. Here, we investigated potential mechanistic links between ceramide as a modulator of NLRP3 inflammasome assembly and the resulting secretion of IL-1β using small bioactive enzyme stimulators and inhibitors of ceramide signaling in wild-type and apoptosis-associated speck-like protein containing a CARD knockout (ASC−/−) primary microglia. To induce the expression of inflammasome components, microglia were primed prior to experiments. Treatment with sodium palmitate (PA) induced de novo ceramide synthesis via modulation of its synthesizing protein serine palmitoyl transferase resulting in increased IL-1β secretion in microglia. Exposure of microglia to the serine palmitoyl transferase-inhibitor l-cycloserine significantly prevented PA-induced IL-1β secretion. Application of the ceramide analogue C2 and the sphingosine-1-phosphate-receptor agonist Fingolimod (FTY720) up-regulated levels of IL-1β and cleaved caspase-1 in wild-type microglia, whereas ASC−/− microglia were unaffected. HPA-12 inhibition of ceramide transport did not affect inflammasome activation. Taken together, our findings reveal a critical role for ceramide as a positive modulator of NLRP3 inflammasome assembly and the resulting release of IL-1β. Many studies have concluded that saturated fatty acids like palmitate and its breakdown product ceramide regulate a number of physiological processes closely associated with inflammation and neurodegenerative disorders within the CNS. Here, we present evidence that ceramide is able to modulate the actions of the NLRP3 inflammasome and the resulting release of Interleukin-1β (IL-1β). Treatment of microglia with agents that induce ceramide signaling increased NLRP3 inflammasome assembly and IL-1β release, whereas disruption of these signaling steps reduced inflammasome activation.
Datum: 26.10.2017


Single cocaine exposure does not alter striatal pre-synaptic dopamine function in mice: an [18F]-FDOPA PET study

Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre-synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and post-synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre-synaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography have revealed impaired pre-synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre-synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15–20 min post treatment (p < 0.001). However, dopamine synthesis capacity in the striatum was not significantly altered by acute cocaine treatment (KiCer: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre-synaptic dopaminergic neurons are not initiated following a single exposure to the drug. Cocaine blocks the reuptake of synaptic dopamine via the dopamine transporter. Here we have used [18F]-FDOPA µPET to determine the effects of acute cocaine exposure on dopamine synthesis and storage in mice. At a dose that causes hyperlocomotor activity, a single exposure to cocaine does not significantly alter the kinetic parameters of pre-synaptic dopamine function in the striatum.
Datum: 26.10.2017


Dimethyl fumarate treatment after traumatic brain injury prevents depletion of antioxidative brain glutathione and confers neuroprotection

Dimethyl fumarate (DMF) is an immunomodulatory compound to treat multiple sclerosis and psoriasis with neuroprotective potential. Its mechanism of action involves activation of the antioxidant pathway regulator Nuclear factor erythroid 2-related factor 2 thereby increasing synthesis of the cellular antioxidant glutathione (GSH). The objective of this study was to investigate whether post-traumatic DMF treatment is beneficial after experimental traumatic brain injury (TBI). Adult C57Bl/6 mice were subjected to controlled cortical impact followed by oral administration of DMF (80 mg/kg body weight) or vehicle at 3, 24, 48, and 72 h after the inflicted TBI. At 4 days after lesion (dal), DMF-treated mice displayed less neurological deficits than vehicle-treated mice and reduced histopathological brain damage. At the same time, the TBI-evoked depletion of brain GSH was prevented by DMF treatment. However, nuclear factor erythroid 2-related factor 2 target gene mRNA expression involved in antioxidant and detoxifying pathways was increased in both treatment groups at 4 dal. Blood brain barrier leakage, as assessed by immunoglobulin G extravasation, inflammatory marker mRNA expression, and CD45+ leukocyte infiltration into the perilesional brain tissue was induced by TBI but not significantly altered by DMF treatment. Collectively, our data demonstrate that post-traumatic DMF treatment improves neurological outcome and reduces brain tissue loss in a clinically relevant model of TBI. Our findings suggest that DMF treatment confers neuroprotection after TBI via preservation of brain GSH levels rather than by modulating neuroinflammation. Dimethyl fumarate (DMF) is an immunomodulatory compound to treat multiple sclerosis and psoriasis. Here, we demonstrate that DMF confers neuroprotection after experimental traumatic brain injury (TBI) in mice. Data show that post-traumatic DMF treatment preserves the brain levels of antioxidant glutathione. DMF may improve the antioxidant capacity and thereby reduce neurotoxic oxidative stress after TBI.
Datum: 26.10.2017


Functional changes in the neural retina occur in the absence of mitochondrial dysfunction in a rodent model of diabetic retinopathy

Diabetic retinopathy is a neurovascular diabetes complication resulting in vision loss. A wealth of literature reports retinal molecular changes indicative of neural deficits, inflammation, and vascular leakage with chronic diabetes, but the mechanistic causes of disease initiation and progression are unknown. Microvascular mitochondrial DNA (mtDNA) damage leading to mitochondrial dysfunction has been proposed to drive vascular dysfunction in retinopathy. However, growing evidence suggests that neural retina dysfunction precedes and may cause vascular damage. Therefore, we tested the hypothesis that neural mtDNA damage and mitochondrial dysfunction are an early initiating factor of neural diabetic retinopathy development in a rat streptozotocin-induced, Type I diabetes model. Mitochondrial function (oxygen consumption rates) was quantified in retinal synaptic terminals from diabetic and non-diabetic rats with paired retinal structural and function assessment (optical coherence tomography and electroretinography, respectively). Mitochondrial genome damage was assessed by identifying mutations and deletions across the mtDNA genome by high depth sequencing and absolute mtDNA copy number counting through digital PCR. Mitochondrial protein expression was assessed by targeted mass spectrometry. Retinal functional deficits and neural anatomical changes were present after 3 months of diabetes and prevented/normalized by insulin treatment. No marked dysfunction of mitochondrial activity, maladaptive changes in mitochondrial protein expression, alterations in mtDNA copy number, or increase in mtDNA damage was observed in conjunction with retinal functional and anatomical changes. These results demonstrate that neural retinal dysfunction with diabetes begins prior to mtDNA damage and dysfunction, and therefore retinal neurodegeneration initiation with diabetes occurs through other, non-mitochondrial DNA damage, mechanisms. Neuronal dysfunction precedes traditional vascular defects in diabetic retinopathy disease progression. In this study neuronal mitochondrial status was examined across functional, proteomic, and genomic domains in rats characterized for neural retinal function and structure. Mitochondrial deficits were not evident at a disease timepoint where neural retinal deficits are evident demonstrating that diabetic retinopathy disease initiation occurs through non-mitochondrial mechanisms.
Datum: 20.10.2017


Regulatory connection between the expression level of classical protein kinase C and pruning of climbing fibers from cerebellar Purkinje cells

Cerebellar Purkinje cells (PCs) express two members of the classical protein kinase C (PKC) subfamily, namely, PKCα and PKCγ. Previous studies on PKCγ knockout (KO) mice have revealed a critical role of PKCγ in the pruning of climbing fibers (CFs) from PCs during development. The question remains as to why only PKCγ and not PKCα is involved in CF synapse elimination from PCs. To address this question, we assessed the expression levels of PKCγ and PKCα in wild-type (WT) and PKCγ KO PCs using PC-specific quantitative real-time reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical analysis. The results revealed that the vast majority of cPKCs in PCs were PKCγ, whereas PKCα accounted for the remaining minimal fraction. The amount of PKCα was not upregulated in PKCγ KO PCs. Lentiviral expression of PKCα in PKCγ KO PCs resulted in a 10-times increase in the amount of PKCα mRNA in the PKCγ KO PCs, compared to that in WT PCs. Our quantification showed that the expression levels of cPKC mRNA in PKCγ KO PCs increased roughly from 1% to 22% of that in WT PCs solely through PKCα expression. The upregulation of PKCα in PKCγ KO PCs significantly rescued the impaired CF synapse elimination. Although both PKCα and PKCγ are capable of pruning supernumerary CF synapses from developing PCs, these results suggest that the expression levels of cPKCs in PKCγ KO PCs are too low for CF pruning. This article is protected by copyright. All rights reserved.
Datum: 19.10.2017


Intra-arterial transplantation of human bone marrow mesenchymal stem cells (hBMMSCs) improves behavioral deficits and alters gene expression in rodent stroke model

Stroke is a multi-factorial polygenic disease and is a major cause of death and adult disability. Administration of bone marrow stem cells protects ischemic rat brain by facilitating recovery of neurological functions. But the molecular mechanism of stem cells action and their effect on gene expression is not well explored. In this study, we have transplanted 1× 106 human bone marrow mesenchymal stem cells (hBMMSCs) in middle cerebral artery occluded (MCAo) adult male Wistar rats through intracarotid artery route at 24 hours after surgery. Motor behavioral tests (rotarod and open field) were performed to assess the changes in motor functions at day 0 and day1, 4, 8 and 14. The expression of studied genes at mRNA and protein level was quantified by using Q-PCR and western blotting, respectively. Further, we have assessed the methylation pattern of promoter of these genes by using methylation-specific PCR. Data was analyzed statistically and correlated. A significant improvement in behavioral deficits was observed in stem cells treated group after 14th day post stroke. Significantly (p<0.05) increased mRNA and protein levels of BDNF and ANP genes in hBMMSCs treated group along with decrease in methylation level at their promoter was observed. On the other hand, significantly decreased mRNA and protein level of TSP1 and WNK1 in hBMMSCs treated group was observed. In conclusion, hBMMSCs administration significantly improves the behavioral deficits by improving motor and locomotor co-ordination. The promoter of TSP1 and WNK1 genes was found to be hyper-methylated in hBMMSCs group resulting in their decreased expression while the promoter of ANP and BDNF was found to be hypo-methylated. This study might shed a light on how hBMMSCs affect the gene expression by modulating methylation status. This article is protected by copyright. All rights reserved.
Datum: 19.10.2017


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


Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma

Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity- and brain-derived neurotrophic factor (BDNF)-dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro-2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice. ER stress transducer, inositol-requiring kinase 1 (IRE1), was activated at postsynapses in response to excitatory synaptic activation. Activated dendritic IRE1 accelerated accumulation of the downstream transcription factor, x-box-binding protein 1 (XBP1), in the nucleus. Interestingly, excitatory synaptic activation-dependent up-regulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1-XBP1 pathway in a protein kinase A-dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A-IRE1-XBP1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE1-XBP1 signaling. Synaptic activity- and BDNF-dependent distinct activation of dendritic IRE1-XBP1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Unfolded protein response (UPR) plays a key role in resolving the accumulation of unfolded proteins as well as the regulation of cellular physiological functions. The goal of this study was to investigate if synaptic activity- and brain-derived neurotrophic factor (BDNF)-dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation, using primary cultured mouse hippocampal neurons and murine neuroblastoma cell lines. Results revealed dendritic inositol-requiring kinase 1 (IRE1) phosphorylation at postsynaptic sites by synaptic activation, followed by accumulation of x-box-binding protein 1 (XBP1) in the nucleus, resulting in induction of Bdnf expression. BDNF drives its own expression via protein kinase A (PKA)-dependent activation of dendritic IRE1-XBP1 signaling. Synaptic activity-and BDNF-dependent distinct activation of dendritic IRE1-XBP1 cascade may comprehensively regulate dendritic extension through BDNF expression.
Datum: 16.10.2017


Vaccination strategies in tauopathies and synucleinopathies

Vaccination therapies constitute potential treatment options in neurodegenerative disorders such as Alzheimer disease or Parkinson disease. While a lot of research has been performed on vaccination against extracellular amyloid β, the focus recently shifted toward vaccination against the intracellular proteins tau and α-synuclein, with promising results in terms of protein accumulation reduction. In this review, we briefly summarize lessons to be learned from clinical vaccination trials in Alzheimer disease that target amyloid β. We then focus on tau and α-synuclein. For both proteins, we provide important data on protein immunogenicity, and put them into context with data available from both animals and human vaccination trials targeted at tau and α-synuclein. Together, we give a comprehensive overview about current clinical data, and discuss associated problems. Vaccination therapies constitute potential treatment options in neurodegenerative disorders such as Alzheimer disease or Parkinson's disease. In this review, we summarize current vaccination strategies against the intracellular proteins tau and α-synuclein from both animal and human vaccination trials. In addition, we comment on lessons learned from clinical vaccination trials in Alzheimer disease targeting amyloid β and discuss potential mechanisms of action.
Datum: 16.10.2017


Alexander George Karczmar (1917–2017)

The neurochemistry community at large and the Advisory Board of The International Symposia on Cholinergic Mechanisms mourn the loss of Alexander George Karczmar, the elected Honorary President of these international symposia, who passed away peacefully in his Chicago home at the age of 100 on August 17, 2017. For many of us Alex was the essence of cholinergic signaling, and personified its versatile power to send messages between the brain and the peripheral tissues and organs, and to connect between body and soul.
Datum: 13.10.2017


Alteration of sphingolipid metabolism as a putative mechanism underlying LPS-induced BBB disruption

Septic encephalopathy with confusion and agitation occurs early during sepsis and contributes to the severity of the disease. A decrease of the sphingosine-1-phosphate (S1P) blood levels has been shown in patients and in animal models of sepsis. The lipid mediator S1P is known to be involved in endothelial barrier function in a context-dependent manner. We utilized LPS injected mice as a model for septic encephalopathy and first performed tracer permeability assays to assess the BBB breakdown in vivo. At time points corresponding to the BBB breakdown post LPS injection, we aimed to characterize the regulation of the sphingolipid signaling pathway at the blood-brain barrier (BBB) during sepsis. We measured sphingolipid concentrations in blood, in mouse brain microvessels (MBMVs), and brain tissue. We also analyzed the expression of S1P receptors, transporters and metabolizing enzymes in MBMVs and brain tissue. Primary mouse brain microvascular endothelial cells (MBMECs) were isolated to evaluate the effects of LPS on transendothelial electrical resistance (TEER) as a measure of permeability in vitro. We observed a relevant decrease of S1P levels after LPS injection in all three compartments (blood, MBMVs, brain tissue) that was accompanied by an increased expression of the S1P receptor type 1 and of sphingosine kinase 1 (SphK1) on the one hand and of the S1P degrading enzymes lipid phosphate phosphatase 1 (LPP1) and S1P phosphatase 1 (Sgpp1) on the other hand, as well as a downregulation of SphK2. Application of LPS to a monolayer of primary MBMECs did not alter TEER, but serum from LPS-treated mice lead to a breakdown of the barrier compared to serum from vehicle-treated mice. We observed profound alterations of the sphingolipid metabolism at the BBB after LPS injection that point towards a therapeutic potential of drugs interfering with this pathway as novel approach for the detrimental overwhelming immune response in sepsis. This article is protected by copyright. All rights reserved.
Datum: 11.10.2017


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


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

Large artery stiffness is a frequent condition that arises with aging, 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 protected by copyright. All rights reserved.
Datum: 09.10.2017


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. 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.
Datum: 27.09.2017


Reduced muscle strength in ether lipid-deficient mice is accompanied by altered development and function of the neuromuscular junction

Inherited deficiency in ether lipids, a subgroup of phospholipids whose biosynthesis needs peroxisomes, causes the fatal human disorder rhizomelic chondrodysplasia punctata. The exact roles of ether lipids in the mammalian organism and, therefore, the molecular mechanisms underlying the disease are still largely enigmatic. Here, we used glyceronephosphate O-acyltransferase knockout (Gnpat KO) mice to study the consequences of complete inactivation of ether lipid biosynthesis and documented substantial deficits in motor performance and muscle strength of these mice. We hypothesized that, probably in addition to previously described cerebellar abnormalities and myelination defects in the peripheral nervous system, an impairment of neuromuscular transmission contributes to the compromised motor abilities. Structurally, a morphologic examination of the neuromuscular junction (NMJ) in diaphragm muscle at different developmental stages revealed aberrant axonal branching and a strongly increased area of nerve innervation in Gnpat KO mice. Post-synaptically, acetylcholine receptor (AChR) clusters colocalized with nerve terminals within a widened endplate zone. In addition, we detected atypical AChR clustering, as indicated by decreased size and number of clusters following stimulation with agrin, in vitro. The turnover of AChRs was unaffected in ether lipid-deficient mice. Electrophysiological evaluation of the adult diaphragm indicated that although evoked potentials were unaltered in Gnpat KO mice, ether lipid deficiency leads to fewer spontaneous synaptic vesicle fusion events but, conversely, an increased post-synaptic response to spontaneous vesicle exocytosis. We conclude from our findings that ether lipids are essential for proper development and function of the NMJ and may, therefore, contribute to motor performance. Read the Editorial Highlight for this article on page 463. Here, we demonstrate deficits in muscle strength in mice that lack ether lipids, a particular group of phospholipids. At the same time, proper development of the neuromuscular junction is impaired. Electrophysiological analysis of neuromuscular transmission indicates that ether lipid deficiency results in fewer spontaneous synaptic vesicle fusion events but grossly normal evoked potentials. We conclude that ether lipids are important for correct development and function of the neuromuscular junction. Read the Editorial Highlight for this article on page 463.
Datum: 25.09.2017


Ether lipids and their elusive function in the nervous system: a role for plasmalogens

In this editorial, we highlight the recent work of Dorninger et al. that demonstrates a reduction in plasmalogens in the motor end plate is associated with a reduction in motor end plate function. This reduction in function is illuminated in reduced muscle function in these mice, corresponding with the reduction in acetylcholine release and in its receptor density observed in these mice.
Datum: 25.09.2017


Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma

Elevated expression of enhancer of zeste homolog 2 (EZH2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase (TERT) promoter mutations. Given the known involvement of TERT and EZH2 in glioma progression, the correlation between the two and subsequently its involvement in metabolic programming was investigated. Inhibition of human telomerase reverse transcriptase either pharmacologically or through genetic manipulation not only decreased EZH2 expression, but also (i) abrogated FASN levels, (ii) decreased de novo fatty acid accumulation, and (iii) increased ataxia-telangiectasia-mutated (ATM) phosphorylation levels. Conversely, diminished TERT and FASN levels upon siRNA-mediated EZH2 knockdown indicated a positive correlation between TERT and EZH2. Interestingly, ATM kinase inhibitor rescued TERT inhibition-mediated decrease in FASN and EZH2 levels. Importantly, TERT promoter mutant tumors exhibited greater microsatellite instability, heightened FASN levels and lipid accumulation. Coherent with in vitro findings, pharmacological inhibition of TERT by costunolide decreased lipid accumulation and elevated ATM expression in heterotypic xenograft glioma mouse model. By bringing TERT-EZH2 network at the forefront as driver of dysregulated metabolism, our findings highlight the non-canonical but distinct role of TERT in metabolic reprogramming and DNA damage responses in glioblastoma. Mutation in telomerase reverse transcriptase (TERT) promoter correlates with poor prognosis in glioblastoma (GBM). As elevated enhancer of zeste homolog 2 (EZH2) and fatty acid synthase (FASN) levels were accompanied by heightened microsatellite instability in TERT-mutant GBMs, their correlations were investigated. Genetic and pharmacological manipulation of TERT indicated the importance of TERT–EZH2 axis in regulating lipid metabolism and ataxia-telangiectasia-mutated (ATM) activation. This study provides better understanding of aberrant metabolic programming in GBM based on distinctive genetic alterations.
Datum: 22.09.2017


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


Role of the GM1 ganglioside oligosaccharide portion in the TrkA-dependent neurite sprouting in neuroblastoma cells

GM1 ganglioside (II3NeuAc-Gg4Cer) is known to promote neurite formation in neuroblastoma cells by activating TrkA-MAPK pathway. The molecular mechanism by which GM1 is involved in the neurodifferentiation process is still unknown, however, in vitro and in vivo evidences have suggested that the oligosaccharide portion of this ganglioside could be involved. Here, we report that, similarly to the entire GM1 molecule, its oligosaccharide II3NeuAc-Gg4, rather than its ceramide (Cer) portion is responsible for the neurodifferentiation process by augmenting neurite elongation and increasing the neurofilament protein expression in murine neuroblastoma cells, Neuro2a. Conversely, asialo-GM1, GM2 and GM3 oligosaccharides are not effective in neurite elongation on Neuro2a cells, whereas the effect exerted by the Fuc-GM1 oligosaccharide (IV2αFucII3Neu5Ac-Gg4) is similar to that exerted by GM1 oligosaccharide. The neurotrophic properties of GM1 oligosaccharide are exerted by activating the TrkA receptor and the following phosphorylation cascade. By photolabeling experiments performed with a nitrophenylazide containing GM1 oligosaccharide, labeled with tritium, we showed a direct interaction between the GM1 oligosaccharide and the extracellular domain of TrkA receptor. Moreover, molecular docking analyses confirmed that GM1 oligosaccharide binds the TrkA-nerve growth factor complex leading to a binding free energy of approx. −11.5 kcal/mol, acting as a bridge able to increase and stabilize the TrkA-nerve growth factor molecular interactions. GM1 ganglioside (II3Neu5Ac-Gg4Cer) is known to promote neurite formation in neuroblastoma cells like N2a cells by activating TrkA-MAPK pathway. This study shows that GM1 modulates TrkA activity by stabilizing the TrkA-NGF complex with its oligosaccharide portion. The complex induces the TrkA phosphorylation and MAPK-pathway activation, triggering the differentiation signaling. These findings provide a new view for the role of the oligosaccharide chain of gangliosides in plasma membrane signaling.
Datum: 13.09.2017


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


Brain endothelial cells induce astrocytic expression of the glutamate transporter GLT-1 by a Notch-dependent mechanism

Neuron-secreted factors induce astrocytic expression of the glutamate transporter, GLT-1 (excitatory amino acid transporter 2). In addition to their elaborate anatomic relationships with neurons, astrocytes also have processes that extend to and envelop the vasculature. Although previous studies have demonstrated that brain endothelia contribute to astrocyte differentiation and maturation, the effects of brain endothelia on astrocytic expression of GLT-1 have not been examined. In this study, we tested the hypothesis that endothelia induce expression of GLT-1 by co-culturing astrocytes from mice that utilize non-coding elements of the GLT-1 gene to control expression of reporter proteins with the mouse endothelial cell line, bEND.3. We found that endothelia increased steady state levels of reporter and GLT-1 mRNA/protein. Co-culturing with primary rat brain endothelia also increases reporter protein, GLT-1 protein, and GLT-1-mediated glutamate uptake. The Janus kinase/signal transducer and activator of transcription 3, bone morphogenic protein/transforming growth factor β, and nitric oxide pathways have been implicated in endothelia-to-astrocyte signaling; we provide multiple lines of evidence that none of these pathways mediate the effects of endothelia on astrocytic GLT-1 expression. Using transwells with a semi-permeable membrane, we demonstrate that the effects of the bEND.3 cell line are dependent upon contact. Notch has also been implicated in endothelia-astrocyte signaling in vitro and in vivo. The first step of Notch signaling requires cleavage of Notch intracellular domain by γ-secretase. We demonstrate that the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester blocks endothelia-induced increases in GLT-1. We show that the levels of Notch intracellular domain are higher in nuclei of astrocytes co-cultured with endothelia, an effect also blocked by N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester. Finally, infection of co-cultures with shRNA directed against recombination signal binding protein for immunoglobulin kappa J, a Notch effector, also reduces endothelia-dependent increases in enhanced green fluorescent protein and GLT-1. Together, these studies support a novel role for Notch in endothelia-dependent induction of GLT-1 expression. Cover Image for this issue: doi. 10.1111/jnc.13825. Signaling from endothelial cells has been shown to affect astrocyte specification and maturation. We show that co-culturing astrocytes with endothelial cells increases expression of the glial glutamate transporter GLT-1 as well as expression of a transcriptional reporter in a contact-dependent mechanism. This increase is dependent on Notch signaling, as inhibition of the Notch pathway by treatment with a γ-secretase inhibitor or knock-down of RBPJ prevents the endothelia-induced increase in GLT-1. Cover Image for this issue: doi. 10.1111/jnc.13825.
Datum: 05.09.2017


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






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