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



γ-Secretase in microglia – Implications for neurodegeneration and neuroinflammation

γ-Secretase is an intramembrane cleaving protease involved in the generation of the Alzheimer's disease (AD) associated amyloid β peptide (Aβ). γ-Secretase is ubiquitously expressed in different organs, and also in different cell types of the human brain. Besides the involvement in the proteolytic generation of Aβ from the amyloid precursor protein, γ-secretase cleaves many additional protein substrates, suggesting pleiotropic functions under physiological and pathophysiological conditions. Microglia exert important functions during brain development and homeostasis in adulthood, and accumulating evidence indicates that microglia and neuroinflammatory processes contribute to the pathogenesis of neurodegenerative diseases. Recent studies demonstrate functional implications of γ-secretase in microglia, suggesting that alterations in γ-secretase activity could contribute to AD pathogenesis by modulation of microglia and related neuroinflammatory processes during neurodegeneration. In this review, we discuss the involvement of γ-secretase in the regulation of microglial functions, and the potential relevance of these processes under physiological and pathophysiological conditions. This article is protected by copyright. All rights reserved.
Datum: 23.09.2017


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 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 (WT) 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 (SPT) resulting in increased IL-1β secretion in microglia. Exposure of microglia to the SPT-inhibitor L-Cycloserine (LCS) 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 WT microglia while 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. This article is protected by copyright. All rights reserved.
Datum: 23.09.2017


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


Corticosterone and exogenous glucose alter blood glucose levels, neurotoxicity, and vascular toxicity produced by methamphetamine

Our previous studies have raised the possibility that altered blood glucose levels may influence and/or be predictive of methamphetamine (METH) neurotoxicity. This study evaluated the effects of exogenous glucose and corticosterone (CORT) pretreatment alone or in combination with METH on blood glucose levels and the neural and vascular toxicity produced. METH exposure consisted of four sequential injections of 5, 7.5, 10, and 10 mg/kg (2 h between injections) D-METH. The three groups given METH in combination with saline, glucose (METH+Glucose), or CORT (METH+CORT) had significantly higher glucose levels compared to the corresponding treatment groups without METH except at 3 h after the last injection. At this last time point, the METH and METH+Glucose groups had lower levels than the non-METH groups, while the METH+CORT group did not. CORT alone or glucose alone did not significantly increase blood glucose. Mortality rates for the METH+CORT (40%) and METH+Glucose (44%) groups were substantially higher than the METH (< 10%) group. Additionally, METH+CORT significantly increased neurodegeneration above the other three METH treatment groups (≈ 2.5-fold in the parietal cortex). Thus, maintaining elevated levels of glucose during METH exposure increases lethality and may exacerbate neurodegeneration. Neuroinflammation, specifically microglial activation, was associated with degenerating neurons in the parietal cortex and thalamus after METH exposure. The activated microglia in the parietal cortex were surrounding vasculature in most cases and the extent of microglial activation was exacerbated by CORT pretreatment. Our findings show that acute CORT exposure and elevated blood glucose levels can exacerbate METH-induced vascular damage, neuroinflammation, neurodegeneration and lethality. This study evaluated exogenous glucose and corticosterone pretreatment to methamphetamine on blood glucose levels and neural/vascular toxicity. Methamphetamine with saline, glucose, or corticosterone had significantly higher glucose levels. Methamphetamine+corticosterone and methamphetamine+glucose mortality rates were substantially higher than methamphetamine. Methamphetamine+corticosterone significantly increased neurodegeneration above other treatments. Neuroinflammation (microglial activation) was associated with degenerating neurons and largely surrounded vasculature after methamphetamine, an effect exacerbated by corticosterone pretreatment. Our findings implicate elevated glucose levels and hyperthermia in methamphetamine-induced neurotoxicity, neurovascular damage, and lethality.
Datum: 21.09.2017


Epigenetics and DNA methylomic profiling in Alzheimer's disease and other neurodegenerative diseases

Recent studies have suggested a role for epigenetic mechanisms in the complex etiology of various neurodegenerative diseases. In this review, we discuss advances that have been made toward understanding the role of epigenetic processes in neurodegenerative disorders, with a particular focus on Alzheimer's disease, where the most extensive studies have been undertaken to date. We provide a brief overview of DNA modifications, followed by a summarization of studies of DNA modifications in Alzheimer's disease and other neurodegenerative diseases. Epigenetic mechanisms have been hypothesized to play a role in a number of different neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. In this review, we provide an overview of current studies performed in the field, with a focus on DNA methylation, before discussing the potential direction of future studies.
Datum: 21.09.2017


Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors

Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca2+ channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT1A receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 μM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca2+] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca2+ entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca2+entry via nAChRs. Sigma-1 receptors are intracellular chaperone proteins that can translocate to the plasma membrane to modulate various ion channels and cellular functions. We investigated the impact of several sigma-1 receptor ligands including fluvoxamine (a selective serotonin reuptake inhibitor) on catecholamine secretion from adrenal chromaffin cells. Our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, sigma-1 receptor ligands inhibited secretion evoked by cholinergic stimulation because of direct block of Ca2+entry via nicotinic acetylcholine receptors.
Datum: 19.09.2017


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


Mst-1 deficiency promotes post-traumatic spinal motor neuron survival via enhancement of autophagy flux

The mammalian Ste20-like kinase 1 (Mst-1) is a serine-threonine kinase and a component of the Hippo tumor suppressor pathway, which reacts to pathologically relevant stress and regulates cell death. However, little is known about its role in spinal cord injury. Here, we found that p-Mst-1, the activated form of Mst-1, was induced in the post-traumatic spinal motor neurons. In vivo evidence demonstrated that Mst-1 deficiency promoted post-traumatic spinal motor neuron survival, Basso mouse scale scores, and synapse survival. Moreover, we found that autophagosome formation and autolysosome degradation enhanced by Mst-1 deficiency were crucial to attenuate the death of injured spinal motor neurons. Taken together, our findings demonstrate that Mst-1 deficiency promotes post-traumatic spinal motor neuron survival via enhancement of autophagy flux. Primary injury occurs immediately after spinal cord injury (SCI), leading to neuron death directly at the lesion site. The pathological stress during the secondary injury will create a hostile environment that lead to further neural death around the primary lesion site. The mammalian Ste20-like kinase 1 (Mst-1) is a serine-threonine kinase and a component of the Hippo tumor suppressor pathway, which reacts to pathologically relevant stress and regulates cell death. We found that Mst-1 deficiency enhanced autophagosome formation and autolysosome degradation in the hostile environment after SCI, through which injured spinal motor neurons adequately degraded toxic protein aggregates, and eventually, led to more motor neuron survival.
Datum: 19.09.2017


Issue Cover (October 2017)

Front cover: The amyloid precursor protein (APP) plays a central role as a cell adhesion molecule in key events of neuronal development, such as migration, neurite outgrowth, growth cone pathfinding and synaptogenesis. Also, APP is overexpressed in Down syndrome individuals due to the extra copy of chromosome 21 and thus it might contribute to the down syndrome intellectual disabilities. The cover image shows the axonal growth cone from Ts65Dn hippocampal neuron (transgenic mice that develop a DS-like condition) cultured on laminin and imaged by TIRF after labeling the actin filaments (green) and APP (red). Analysis performed with Ts65Dn mice revealed enrichment of APP in the cortex and within neurons, in the axonal growth cone. In this context, hippocampal pyramidal neurons derived from Ts65Dn mice and cultured on laminin substrate exhibit aberrant growth cones with large adhesive areas and abundant filopodia.This Review followed a CAEN Return Home Grant. Read the full article ‘The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system’ by L. J. Sosa, A. Cáceres, S. Dupraz, M. Oksdath, S. Quiroga and A. Lorenzo (J. Neurochem. 2017, vol. 143 (1), pp. 11–29) on doi: 10.1111/jnc.14122Read the Editorial Highlight ‘A mobile APP for sharing contacts on your cell’ on doi: 10.1111/jnc.14115.
Datum: 18.09.2017


Issue Information


Datum: 18.09.2017


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

Cocaine is a recreational drug of abuse that binds to the dopamine transporter (DAT), preventing reuptake of dopamine into presynaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and postsynaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on presynaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography (PET) have revealed impaired presynaptic 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 μ-PET imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of presynaptic dopamine function. We show that a dose of 20mg/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 min−1 vs. 0.0112 min−1 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 presynaptic dopaminergic neurons are not initiated following a single exposure to the drug. This article is protected by copyright. All rights reserved.
Datum: 18.09.2017


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. This article is protected by copyright. All rights reserved.
Datum: 17.09.2017


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 post synapses 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 upregulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1-XBP1 pathway in a protein kinase A (PKA)-dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the PKA-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. This article is protected by copyright. All rights reserved.
Datum: 16.09.2017


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

Dimethyl fumarate (DMF) is an immunomodulatory therapeutic for 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 (Nrf2) 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 h, 24 h, 48 h 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, Nrf2 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. This article is protected by copyright. All rights reserved.
Datum: 16.09.2017


MicroRNA-212 inhibits oligodendrocytes during maturation by down-regulation of differentiation-associated gene expression

MicroRNA-212 (mir-212) has been reported to regulate neuronal development and functioning. However, its expression and function in glia are not yet known. Here, we demonstrate that the level of microRNA-212 (mir-212) was reduced in spinal cord lesion site at 1 week and 1 month after a contusive spinal cord injury. In addition to its expression in neurons, mir-212 expression was detected in oligodendrocytes (OLGs) and glial progenitor cells (GPCs) in adult CNS. The addition of antagomir-212 to reduce mir-212 expression enabled to improve the cell process outgrowth of OLGs along with the up-regulation of the genes associated with OLG differentiation and maturation, including OLIG1, SOX10, myelin basic protein (MBP), and proteolipid protein 1 (PLP1). In contrast, these genes were significantly down-regulated by an increased expression of mir-212 in GPCs or in OLG progenitor cells (OPCs) through lentivirus-mediated gene delivery approach. Moreover, we found that PLP1 was the direct target molecule of mir-212. Furthermore, mir-212 over-expression diminished the protein production of OLGs markers including 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase), MBP, and PLP. Additionally, mir-212 over-expression decreased the number of mature OLGs expressing MBP, and the expression of galactocerebroside (GC). Complementary studies in a hippocampal neuron-OLG co-culture model and an ex vivo cerebellar slice system indicated that OLGs derived from GPCs with mir-212 over-expression exhibited decreased ability to interact with neuronal axons. Collectively, our findings demonstrate that mir-212 repressed the expression of OLG maturation-associated proteins and inhibited OLG cell process extension, indicating that mir-212 has negative regulatory effect on OLG lineage progression. MicroRNA-212 (mir-212) can regulate neuronal development and functioning. However, its expression and function in glia are not yet known. This report shows that spinal cord injury and interferon-γ (other undefined molecules) can reduce mir-212 expression in oligodendrocytes. Furthermore, mir-212 can suppress oligodendrocyte maturation with the reduction in oligodendrocyte differentiation-associated genes (OLIG1, OLIG2, and SOX10) and maturation proteins (MBP and PLP).
Datum: 14.09.2017


Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice

Post-stroke angiogenesis facilitates neurovascular remodeling process and promotes neurological recovery. Proangiogenic effects of Salvianolic acids (Sals) have been reported in various ischemic disorders. However, the underlying mechanisms are still poorly understood. Previous studies of our laboratory have demonstrated that activating Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the protection against cerebral ischemia/reperfusion injury. In this study, we investigated the impacts of Sals on angiogenesis and long-term neurological recovery after ischemic stroke as well as the potential mechanisms. Male mice subjected to permanent distal middle cerebral artery occlusion were administrated with Sals, 5-bromo-2′-deoxyuridine, and JAK2 inhibitor AG490 once daily from day 1 to day 14 after distal middle cerebral artery occlusion. Compared with the control group, Sals treatment significantly improved neurological recovery at day 14 and 28 after ischemic stroke. Sals enhanced post-stroke angiogenesis, pericytes and astrocytic endfeet covered ratio in the peri-infarct area. The JAK2/STAT3 signaling pathway was activated by Sals in the angiogenesis process, and inhibition of JAK2/STAT3 signaling blocked the effects of Sals on post-stroke angiogenesis and neurological recovery as well as abolished the mediation of proangiogenic factors. In summary, these data suggest that Sals administration enhances cerebral angiogenesis and promotes neurological recovery after ischemic stroke, mediated by the activation of JAK2/STAT3 signaling pathway. Post-stroke angiogenesis contributes to long-term neurological recovery. We demonstrated that Salvianolic acids (Sals) significantly enhanced angiogenesis and improved neurological recovery in ischemic brain. These effects may be dependent on the activation of JAK2/STAT3 signaling pathway which further regulated vascular endothelial growth factor, Ang-1, and Ang-2 expression. It may represent a therapeutic target and provide an alternative strategy for potential clinical trials.
Datum: 14.09.2017


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 (STZ)-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. This article is protected by copyright. All rights reserved.
Datum: 13.09.2017


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 (NGS) technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Out 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 due to 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 NGS is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations. This article is protected by copyright. All rights reserved.
Datum: 13.09.2017


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, 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 MRI 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 algorithms. The patients discussed in this review are derived from published studies. Biomarkers aid in early diagnosis before the disease process have 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 protected by copyright. All rights reserved.
Datum: 13.09.2017


TRPC6 expression in neurons is differentially regulated by NR2A- and NR2B-containing NMDA receptors

The expression of transient receptor potential canonical 6 (TRPC6) in central nervous system (CNS) is important for neuronal functions and certain neural disorders. However, the regulatory mechanism of TRPC6 expression in neurons is still obscure. In the current study, we show that TRPC6 expression in the primary cultured cortical neurons is bidirectionally regulated by glutamate. Activation of NR2A-containing NMDARs induces TRPC6 transcription through a calcineurin-dependent pathway. In contrast, activation of NR2B-containing NMDARs causes TRPC6 degradation through calpain. Thus, TRPC6 expression in neurons is regulated by glutamate in a bidirectional manner that is dependent on NR2A and NR2B. This article is protected by copyright. All rights reserved.
Datum: 13.09.2017


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


Enhanced motivation to alcohol in transgenic mice expressing human α-synuclein

α-Synuclein (αSYN) is the neuropathological hallmark protein of Parkinson's disease (PD) and related neurodegenerative disorders. Moreover, the gene encoding αSYN (SNCA) is a major genetic contributor to PD. Interestingly, independent genome-wide association studies also identified SNCA as the most important candidate gene for alcoholism. Furthermore, single-nucleotide-polymorphisms have been associated with alcohol-craving behavior and alcohol-craving patients showed augmented αSYN expression in blood. To investigate the effect of αSYN on the addictive properties of chronic alcohol use, we examined consumption, motivation, and seeking responses induced by environmental stimuli and relapse behavior in transgenic mice expressing the human mutant [A30P]αSYN throughout the brain. The primary reinforcing effects of alcohol under operant self-administration conditions were increased, while consumption and the alcohol deprivation effect were not altered in the transgenic mice. The same mice were subjected to immunohistochemical measurements of immediate-early gene inductions in brain regions involved in addiction-related behaviors. Acute ethanol injection enhanced immunostaining for the phosphorylated form of cAMP response element binding protein in both amygdala and nucleus accumbens of αSYN transgenic mice, while in wild-type mice no effect was visible. However, at the same time, levels of cFos remain unchanged in both genotypes. These results provide experimental confirmation of SNCA as a candidate gene for alcoholism in addition to its known link to PD. α-Synuclein (αSYN) is known for its implication with Parkinson's disease. Moreover, αSYN is becoming recognized for an involvement in alcoholism, both in animal models and human patients. We tested whether transgenic over-expression of αSYN in mice would affect responses to ethanol. Indeed, αSYN transgenic mice had a higher motivation for ethanol. Also, ethanol injections caused higher induction of pCREB in brain regions involved in alcohol addictive behavior. This study lends further support to the linkage of αSYN to alcoholism.
Datum: 13.09.2017


Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells

Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration. Production of VEGF and macrophage recruitment by retinal pigment epithelial cells (RPE) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase (SR) is expressed in retinal neurons and glial cells, and its product, D-serine, is an endogenous co-agonist of N-methyl-D-aspartate receptor (NMDAR). Activation of the receptor results in production of nitric oxide (.NO), a molecule that promotes retinal and choroidal neovascularization. These observations suggest possible roles of SR in CNV. With laser-injured CNV mice, we found that inactivation of SR-coding gene (Srrnull) significantly reduced CNV volume, neovascular density, and invading macrophages. We exploited the underlying mechanism in vivo and ex vivo. RPE from wild-type (WT) mice expressed SR. To explore the possible downstream target of SR inactivation, we showed that choroid/RPE homogenates extracted from laser-injured Srrnull mice contained less inducible nitric oxide synthase (iNOS) and decreased phospho-VEGFR2 compared to amounts in WT mice. In vitro, inflammation-primed WT RPEs expressed more iNOS, produced more .NO and VEGF than did inflammation-primed Srrnull RPEs. When co-cultured with inflammation-primed Srrnull RPE, significantly fewer RF/6A-a cell line of choroidal endothelial cell (CEC), migrated to the opposite side of the insert membrane than did cells co-cultured with pre-treated WT RPE. Altogether, SR deficiency reduces RPE response to laser-induced inflammatory stimuli, resulting in decreased production of a cascade of pro-angiogenic cytokines, including .NO and VEGF, and reduced macrophage recruitment, which contribute synergistically to attenuated angiogenesis. This article is protected by copyright. All rights reserved.
Datum: 11.09.2017


LPA1 is a key mediator of intracellular signalling and neuroprotection triggered by tetracyclic antidepressants in hippocampal neurons

Both lysophosphatidic acid (LPA) and antidepressants have been shown to affect neuronal survival and differentiation, but whether LPA signalling participates in the action of antidepressants is still unknown. In this study, we examined the role of LPA receptors in the regulation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activity and neuronal survival by the tetracyclic antidepressants, mianserin and mirtazapine in hippocampal neurons. In HT22 immortalized hippocampal cells, antidepressants and LPA induced a time- and concentration-dependent stimulation of ERK1/2 phosphorylation. This response was inhibited by either LPA1 and LPA1/3 selective antagonists or siRNA-induced LPA1 down-regulation, and enhanced by LPA1 over-expression. Conversely, the selective LPA2 antagonist H2L5186303 had no effect. Antidepressants induced cyclic AMP response element binding protein phosphorylation and this response was prevented by LPA1 blockade. ERK1/2 stimulation involved pertussis toxin-sensitive G proteins, Src tyrosine kinases and fibroblast growth factor receptor (FGF-R) activity. Tyrosine phosphorylation of FGF-R was enhanced by antidepressants through LPA1. Serum withdrawal induced apoptotic death, as indicated by increased annexin V staining, caspase activation and cleavage of poly-ADP-ribose polymerase. Antidepressants inhibited the apoptotic cascade and this protective effect was curtailed by blockade of either LPA1, ERK1/2 or FGF-R activity. Moreover, in primary mouse hippocampal neurons, mianserin acting through LPA1 increased phospho-ERK1/2 and protected from apoptosis induced by removal of growth supplement. These data indicate that in neurons endogenously expressed LPA1 receptors mediate intracellular signalling and neuroprotection by tetracyclic antidepressants. We show that in HT22 immortalized hippocampal cells and primary hippocampal neurons, the tetracyclic antidepressants, mianserin and mirtazapine trigger ERK1/2 phosphorylation and protect from apoptosis induced by removal of growth supplement through activation of the lysophosphatidic acid receptor LPA1. In HT22 cells, antidepressant-activated LPA1 up-regulates fibroblast growth factor receptor activity to induce pro-survival signalling via ERK1/2 and CREB. The data indicate that LPA1 is a critical component of tetracyclic antidepressant-induced neuroprotection.
Datum: 11.09.2017


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 MRI scanner to assess brain perfusion, integrity and functional connectivity. To assess brain plasticity, inflammation and vascular integrity, immunohistochemistry was performed after sacrifice 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 stroked females seem more modest in comparison to previously investigated stroked male 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 protected by copyright. All rights reserved.
Datum: 09.09.2017


MicroRNA-27a-3p Suppression of PPAR-γ Contributes to Cognitive Impairments Resulting from Sevoflurane Treatment

Sevoflurane is the most widely used anaesthetic administered by inhalation. Exposure to sevoflurane in neonatal mice can induce learning deficits and abnormal social behaviours. MicroRNA (miR)-27a-3p, a short, noncoding RNA that functions as a tumour suppressor, is upregulated after inhalation of anaesthetic, and peroxisome proliferator-activated receptor γ (PPARγ) is one of its target genes. The objective of this study was to investigate how the miR-27a-3p–PPARγ interaction affects sevoflurane-induced neurotoxicity. A luciferase reporter assay was employed to identify the interaction between miR-27a-3p and PPARγ. Primary hippocampal neuron cultures prepared from embryonic day 0 C57BL/6 mice, were treated with miR-27a-3p or a PPARγ agonist to determine the effect of miR-27a-3p and PPARγ on sevoflurane-induced cellular damage. Cellular damage was assessed by a flow cytometry assay to detect apoptotic cells, immunofluorescence to detect reactive oxygen species, western blotting to detect NOX1/4 and ELISA to measure inflammatory cytokine levels. In vivo experiments were performed using a sevoflurane-induced anaesthetic mouse model to analyse the effects of miR-27a-3p on neurotoxicity by measuring the number of apoptotic neurons using the TUNEL method, and learning and memory function by employing the Morris water maze test. Our results revealed that PPARγ expression was downregulated by miR-27a-3p following sevoflurane treatment in hippocampal neurons. Downregulation of miR-27a-3p expression decreased sevoflurane-induced hippocampal neuron apoptosis by decreasing inflammation and oxidative stress-related protein expression through the upregulation of PPARγ. In vivo tests further confirmed that inhibition of miR-27a-3p expression attenuated sevoflurane-induced neuronal apoptosis, and learning and memory impairment. Our findings suggest that downregulation of miR-27a-3p expression ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-γ signalling pathway. MicroRNA-27a-3p may therefore be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity. This article is protected by copyright. All rights reserved.
Datum: 07.09.2017


Specific rescue by ortho-hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB

The statin atorvastatin (ATV) given as a post-treatment has been reported beneficial in stroke, although the mechanisms involved are not well understood so far. Here we investigated in vitro the effect of post-treatment with ATV and its main bioactive metabolite ortho-hydroxy ATV (o-ATV) on neuroprotection after oxygen and glucose deprivation (OGD), and the role of the pro-survival cAMP response element-binding protein (CREB). Post-OGD treatment of primary cultures of rat cortical neurons with o-ATV, but not ATV, provided neuroprotection to a specific subset of cortical neurons that were large and positive for glutamic acid decarboxylase (large-GAD(+) neurons, GABAergic). Significantly, only these GABAergic neurons showed an increase in phosphorylated CREB (pCREB) early after neuronal cultures were treated post-OGD with o-ATV. We found that o-ATV, but not ATV, increased the neuronal uptake of glutamate from the medium; this provides a rationale for the specific effect of o-ATV on pCREB in large-GABAergic neurons, which have a higher ratio of synaptic (pCREB-promoting) vs extrasynaptic (pCREB-reducing) N-methyl-D-aspartate (NMDA) receptors (NMDAR) than that of small-non-GABAergic neurons. When we pharmacologically increased pCREB levels post-OGD in non-GABAergic neurons, through the selective activation of synaptic NMDAR, we observed as well long-lasting neuronal survival. We propose that the statin metabolite o-ATV given post-OGD boosts the intrinsic pro-survival factor pCREB in large-GABAergic cortical neurons in vitro, this contributing to protect them from OGD. This article is protected by copyright. All rights reserved.
Datum: 07.09.2017


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. Due to 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 serum with a strong affinity for Aβ42 protofibrils. The anti-serum, 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. This article is protected by copyright. All rights reserved.
Datum: 07.09.2017


ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine

To identify neuropeptides that are regulated by cocaine, we used a quantitative peptidomic technique to examine the relative levels of neuropeptides in several regions of mouse brain following daily intraperitoneal administration of 10 mg/kg cocaine or saline for seven days. A total of 102 distinct peptides were identified in one or more of the following brain regions: nucleus accumbens, caudate putamen, frontal cortex, and ventral tegmental area. None of the peptides detected in the caudate putamen or frontal cortex were altered by cocaine administration. Three peptides in the nucleus accumbens and seven peptides in the ventral tegmental area were significantly decreased in cocaine-treated mice. Five of these ten peptides are derived from proSAAS, a secretory pathway protein and neuropeptide precursor. To investigate whether proSAAS peptides contribute to the physiological effects of psychostimulants, we examined acute responses to cocaine and amphetamine in the open field with wild-type (WT) and proSAAS knockout (KO) mice. Locomotion was stimulated more robustly in the WT compared to mutant mice for both psychostimulants. Behavioral sensitization to amphetamine was not maintained in proSAAS KO mice and these mutants failed to sensitize to cocaine. To determine whether the rewarding effects of cocaine were altered, mice were tested in conditioned place preference (CPP). Both WT and proSAAS KO mice showed dose-dependent CPP to cocaine that was not distinguished by genotype. Taken together, these results suggest that proSAAS-derived peptides contribute differentially to the behavioral sensitization to psychostimulants, while the rewarding effects of cocaine appear intact in mice lacking proSAAS. This article is protected by copyright. All rights reserved.
Datum: 07.09.2017


Ulinastatin inhibited sepsis-induced spinal inflammation to alleviate peripheral neuromuscular dysfunction in an experimental rat model of neuromyopathy

Sepsis initiates a neuroinflammatory cascade that contributes to spinal cord inflammation and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of this cascade. In this study, we tested the hypothesis that ulinastatin (ULI) inhibits sepsis-induced spinal inflammation to alleviate peripheral neuromuscular dysfunction through the TLR4/myeloid differentiation factor 88 (MyD88)/NF-κB signaling pathway. Muscular function, spinal cord water content, and cytokine levels of spinal cord were tested in TLR4-inhibited rats subjected to cecal ligation and puncture (CLP). The normal rats were intrathecally injected with different concentrations of ULI or normal saline 60 min before CLP. At 24 h after CLP, the activation of microglia/macrophage was detected by immunofluorescence staining; and the cytokines were assayed by ELISA. The protein expression level of the TLR4 and its downstream effectors (MyD88 and NF-κB), the neuregulin-1, and the γ- and α7-nicotinic acetylcholine receptor was measured using western blotting. The protein expression of TLR4 in the spinal cord reached a maximum at 24 h post-CLP. Compared to the sham rats, the TLR4-inhibited rats showed attenuated functional impairment and cytokine release. ULI (5000 U/kg ) treatment pre-CLP significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release in septic rats. Furthermore, the levels of TLR4, MyD88, and NF-κB and the expression level of γ-/α7-nicotinic acetylcholine receptors also decreased after ULI treatment. ULI administration may improve patient outcome by reducing the spinal inflammation through a mechanism involving the TLR4/MyD88/NF-κB signaling in sepsis. Sepsis initiates a neuroinflammatory cascade that contributes to spinal cord inflammation and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of this cascade. Here, we show that the ulinastatin inhibited the TLR4/MyD88/nuclear factor-kappa B (NF-κB) signals to alleviate the neuromuscular dysfunction. Ulinastatin also reduces the expression of TNF-α and IL-6 in microglia/macrophage during sepsis. We propose that this may be an important mechanism through which ulinastatin improves outcomes following sepsis.
Datum: 06.09.2017


The aberrantly expressed long non-coding RNA in the substantia nigra and corpus striatum of Nrf2-knockout mice

Nuclear factor erythroid 2 like 2 (Nrf2) functions as a neuroprotective agent in Parkinson's disease (PD). This study aimed to investigate the key long non-coding RNAs (lncRNAs) correlated with Nrf2, which might provide valuable information for the exploration of pathogenesis of PD. The lncRNA and mRNA expression profiling of substantia nigra and corpus striatum of Nrf2 (−/−) mice model was obtained from microarray analysis. The animal experiments conducted for this study were approved by the ethics committee of Hebei Medical University. Bioinformatics analyses were conducted, including differentially expressed lncRNAs/mRNA (differentially expressed lncRNA, DEL/differentially expressed mRNA, DEM) identification, DEL-DEM coexpression network construction, and biological functions prediction. Quantitative real-time polymerase chain reaction (qRT-PCR) was subjected to validate abnormally expressed DELs and DEMs in the substantia nigra and corpus striatum of Nrf2 (−/−) mice model. A total of 48 DELs (37 down-regulated and 11 up-regulated) were identified both in Nrf2 (−/−) substantia nigra and corpus striatum; 96 DEMs and 643 DEMs were identified in the substantia nigra and corpus striatum, respectively. DEL-DEM coexpressed network was constructed. LncRNA AK076880, AK036620, and AK020330 had high connectivity with DEMs both in the substantia nigra and corpus striatum. These DEMs were significantly enriched in signaling pathways such as the calcium signaling pathway, Huntington's disease, Alzheimer's disease, mitogen-activated protein kinase (MAPK) signaling pathway, and the Wnt signaling pathway. Generally, qRT-PCR validation results of selected DEMs and DELs were consistent with microarray data. The dysregulated DELs and DEMs in the substantia nigra and corpus striatum of Nrf2 (−/−) mice were identified. Our results might provide useful information for further exploring the pathogenesis mechanism of PD. Nuclear factor erythroid 2 like 2 (Nrf2) plays an important role in Parkinson's disease. The long non-coding RNAs (lncRNA) and mRNA expression profiling of substantia nigra and corpus striatum in Nrf2 (−/−) mice and Nrf2 (+/+) mice model was obtained from microarray analysis. Compared to Nrf2 (+/+) mice, we obtained the differentially expressed lnRNAs/mRNAs (DELs/DEMs) in substantia nigra and corpus striatum of Nrf2 (−/−) mice. Based on the coexpression DEL-DEM network, functional annotation and qRT-PCR validation of expression, we obtained key DELs and DEMs in Nrf2 (−/−) mice. Our results might provide useful information for further exploring the pathogenesis mechanism of Parkinson's disease.
Datum: 06.09.2017


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. 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.
Datum: 05.09.2017


Metal chelator EGCG attenuates Fe(III)-induced conformational transition of α-synuclein and protects AS-PC12 cells against Fe(III)-induced death

The fibrillation and aggregation of α-synuclein (AS), along with the conformational transition from random coil to β-sheet, are the critical steps in the development of Parkinson's disease (PD). It is acknowledged that iron accumulation in the brain may lead to the fibrillation of AS. However, (-)-epigallocatechin gallate (EGCG) can penetrate the blood–brain barrier, chelate metal ions, and inhibit the fibrillation of amyloid proteins. Therefore, EGCG is warranted to be investigated for its potential to cure amyloid-related diseases. In the present work, we sought to study the effects of EGCG on Fe(III)-induced fibrillation of AS on both molecular and cellular levels. We demonstrate that Fe(III) interacts with the amino residue of Tyr and Ala of AS, then accelerates the fibrillation of AS, and increases intracellular reactive oxygen species (ROS) in the AS transduced-PC12 cells (AS-PC12 cells). However, EGCG significantly inhibits this process by chelating Fe(III) and protects AS-PC12 cells against the toxicity induced by ROS and β-sheet-enriched AS fibrils. These findings yield useful information that EGCG might be a promising drug to prevent and treat the neurodegenerative diseases. The fibrillation and aggregation of α-synuclein (AS), along with the conformational transition from random coil to β-sheet, are the critical steps in the development of Parkinson's disease (PD). In this issue, we demonstrate that Fe(III) accelerates the secondary structural transition of α-synuclein (AS) from random coil to β-sheet and fibrillation. Meanwhile, (-)-epigallocatechin gallate (EGCG), which can penetrate the blood–brain barrier attenuates the Fe(III)-induced conformational transition of AS and decreases the Fe(III)-induced AS-PC12 cell death. Our findings suggest that EGCG may protect neurons against Fe(III)-induced neurotoxicity, which is a potential strategy for neurodegenerative diseases.
Datum: 05.09.2017


Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia

Schizophrenia (SCZ) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (PFC). Because these cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (MAM) model for SCZ. Specifically, we hypothesize that N-methyl-D-aspartate receptor (NMDAR) hypofunction is attributable to reductions in the NR2B subunit through aberrant epigenetic regulation of gene expression, resulting in deficient synaptic physiology and PFC-dependent cognitive dysfunction, a hallmark of SCZ. Using western blot and whole-cell patch-clamp electrophysiology, we found that the levels of synaptic NR2B protein are significantly decreased in juvenile MAM animals, and the function of NMDARs is substantially compromised. Both NMDA-mEPSCs and synaptic NMDA-eEPSCs are significantly reduced in prelimbic PFC (plPFC). This protein loss during the juvenile period is correlated with an aberrant increase in enrichment of the epigenetic transcriptional repressor RE1-silencing transcription factor (REST) and the repressive histone marker H3K27me3 at the Grin2b promoter, as assayed by ChIP-quantitative polymerase chain reaction. Glutamate hypofunction has been a prominent hypothesis in the understanding of SCZ pathology; however, little attention has been given to the NMDAR system in the developing PFC in models for SCZ. Our work is the first to confirm that NMDAR hypofunction is a feature of early postnatal development, with epigenetic hyper-repression of the Grin2b promoter being a contributing factor. The selective loss of NR2B protein and subsequent synaptic dysfunction weakens plPFC function during development and may underlie early cognitive impairments in SCZ models and patients. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14133. Glutamate hypofunction has been a prominent hypothesis in schizophrenia pathology; however, when and how NMDAR dysfunction occurs is unknown. We report that NMDAR hypofunction is a feature of early postnatal development. Epigenetic hyper-repression of the Grin2b promoter and subsequent loss of NR2B protein and synaptic NMDAR hypofunction weakens plPFC function. This may underlie early cognitive impairments in schizophrenia. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14133.
Datum: 05.09.2017


The methylazoxymethanol acetate rat model: molecular and epigenetic effect in the developing prefrontal cortex

This Editorial highlights an article by Gulchina and colleagues in the current issue of the Journal of Neurochemistry, in which the authors describe molecular and epigenetic changes in the developing prefrontal cortex of the rats exposed to methylazoxymethanol acetate (MAM). They found an NMDAR hypofunction present in the prefrontal cortex of juvenile MAM rats which was associated with abnormal epigenetic regulation of the Grin2b gene. These changes may be related to early cognitive impairments observed in MAM rats and schizophrenia patients.
Datum: 05.09.2017


‘Prion-like’ propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum

The M83 transgenic mouse is a model of human synucleinopathies that develops severe motor impairment correlated with accumulation of the pathological Ser129-phosphorylated α-synuclein (α-synP) in the brain and spinal cord. M83 disease can be accelerated by intracerebral inoculation of brain extracts from sick M83 mice. This has also recently been described using peripheral routes, injecting recombinant preformed α-syn fibrils into the muscle or the peritoneum. Here, we inoculated homozygous and/or hemizygous M83 neonates via the intraperitoneal and/or intracerebral routes with two different brain extracts: one from sick M83 mice inoculated with brain extract from other sick M83 mice, and the other derived from a human multiple system atrophy source passaged in M83 mice. Detection of α-synP using ELISA and western blot confirmed the disease in mice. The distribution of α-synP in the central nervous system was similar, independently of the inoculum or inoculation route, consistent with previous studies describing M83 disease. ELISA tests revealed higher levels of α-synP in homozygous than in hemizygous sick M83 mice, at least after IC inoculation. Interestingly, the immunoreactivity of α-synP detected by ELISA was significantly lower in M83 mice inoculated with the multiple system atrophy inoculum than in M83 mice inoculated with the M83 inoculum, at the first two passages. ‘Prion-like’ propagation of the synucleinopathy up to the clinical disease was accelerated by both intracerebral and intraperitoneal inoculations of brain extracts from sick mice. This acceleration, however, depends on the levels of α-syn expression by the mouse and the type of inoculum. The transgenic M83 mouse is a model of human synucleinopathies. M83 mice develop a severe motor impairment, associated with the accumulation of pathological Ser129-phosphorylated α-synuclein (α-synP) in the brain and the spinal cord. Here, we show that intraperitoneal inoculation of sick M83 brain homogenate accelerates the M83 disease. The accumulation of α-synP detected by ELISA tests depends on the level of expression of the α-synuclein in the mouse brain and the type of inoculum used.
Datum: 05.09.2017


Models for discovery of targeted therapy in genetic epileptic encephalopathies

Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies. We review the potential for the development of targeted therapies for the genetic epileptic encephalopathies, severe early onset syndromes presenting with refractory seizures and developmental delay. Using the example of ion channels, we address the available and emerging experimental models and how they can identify specific molecular and cellular targets for the novel disease-based treatments of severely affected patients.
Datum: 05.09.2017


p75 neurotrophin receptor interacts with BACE1 and promotes its 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. This article is protected by copyright. All rights reserved.
Datum: 04.09.2017


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 towards vaccination against the intracellular proteins tau and α-synuclein, with promising results in terms of protein accumulation reduction. In the current 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. This article is protected by copyright. All rights reserved.
Datum: 04.09.2017


A modulatory role of the Rax homeobox gene in mature pineal gland function: Investigating the photoneuroendocrine circadian system of a Rax conditional knockout mouse

The retinal and anterior neural fold homeobox gene (Rax) controls development of the eye and the forebrain. Postnatal expression of Rax in the brain is restricted to the pineal gland, a forebrain structure devoted to melatonin synthesis. The role of Rax in pineal function is unknown. In order to investigate the role of Rax in pineal function while circumventing forebrain abnormalities of the global Rax knockout, we generated an eye and pineal-specific Rax conditional knockout mouse. Deletion of Rax in the pineal gland did not affect morphology of the gland, suggesting that Rax is not essential for pineal gland development. In contrast, deletion of Rax in the eye generated an anophthalmic phenotype. In addition to the loss of central visual pathways, the suprachiasmatic nucleus of the hypothalamus housing the circadian clock was absent, indicating that the retinohypothalamic tract is required for the nucleus to develop. Telemetric analyses confirmed the lack of a functional circadian clock. Arylalkylamine N-acetyltransferase (Aanat) transcripts, encoding the melatonin rhythm-generating enzyme, were undetectable in the pineal gland of the Rax conditional knockout under normal conditions, whereas the paired box 6 homeobox gene, known to regulate pineal development, was up-regulated. By injecting isoproterenol, which mimics a nocturnal situation in the pineal gland, we were able to induce pineal expression of Aanat in the Rax conditional knockout mouse, but Aanat transcript levels were significantly lower than those of Rax-proficient mice. Our data suggest that Rax controls pineal gene expression and via Aanat may modulate melatonin synthesis. The RAX transcription factor modulates AANAT levels in the rodent pinealocyte. Norepinephrine released from sympathetic nerve fibers at night increases Rax homeobox gene expression in the pinealocyte of the pineal gland. Norepinephrine is known to stimulate transcription of the Aanat gene inducing conversion of serotonin to melatonin. The results presented here suggest that the RAX transcription factor facilitates norepinephrine-induced Aanat expression and thus modulates nocturnal melatonin synthesis.
Datum: 31.08.2017


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


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 protected by copyright. All rights reserved.
Datum: 21.08.2017


Regulation of synaptic acetylcholine concentrations by acetylcholine transport in rat striatal cholinergic transmission

In addition to hydrolysis by acetylcholine esterase (AChE), acetylcholine (ACh) is also directly taken up into brain tissues. In this study, we examined whether the uptake of ACh is involved in the regulation of synaptic ACh concentrations. Superfusion experiments with rat striatal segments pre-incubated with [3H]choline were performed using an ultra-mini superfusion vessel, which was developed to minimize superfusate retention within the vessel. Hemicholinium-3 (HC-3) at concentrations less than 1 μM, selectively inhibited the uptake of [3H]choline by the high affinity-choline transporter 1 and had no effect on basal and electrically evoked [3H]efflux in superfusion experiments. In contrast, HC-3 at higher concentrations, as well as tetraethylammonium (>10 μM), which inhibited the uptake of both [3H]choline and [3H]ACh, increased basal [3H]overflow and potentiated electrically evoked [3H]efflux. These effects of HC-3 and tetraethylammonium were also observed under conditions where tissue AChE was irreversibly inactivated by diisopropylfluorophosphate. Specifically, the potentiation of evoked [3H]efflux was significantly higher in AChE-inactivated preparations and was attenuated by atropine. On the other hand, striatal segments pre-incubated with [3H]ACh failed to increase [3H]overflow in response to electrical stimulation. These results show that synaptic ACh concentrations are significantly regulated by the postsynaptic uptake of ACh, as well as by AChE hydrolysis and modulation of ACh release mediated through presynaptic muscarinic ACh receptors. In addition, these data suggest that the recycling of ACh-derived choline may be minor in cholinergic terminals. This study reveals a new mechanism of cholinergic transmission in the central nervous system. In central cholinergic transmission, synaptic concentration of acetylcholine (ACh) is significantly regulated by postsynaptic uptake of ACh through putative ACh transporter (AChT), hydrolysis of ACh by acetylcholine esterase (AChE) and autoregulation of presynaptic ACh release by presynaptic ACh receptors (AChRs). ACh-derived choline may not be effectively recycled for ACh synthesis.
Datum: 18.08.2017


Promoter IV-BDNF deficiency disturbs cholinergic gene expression of CHRNA5, CHRM2, and CHRM5: effects of drug and environmental treatments

Brain-derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity-dependent BDNF expression affects specific cholinergic gene expression remains unclear. This study addressed this question by determining mRNA levels of 22 acetylcholine receptor subunits, the choline transporter (CHT), and the choline acetyltransferase (ChAT) in mice deficient in activity-dependent BDNF via promoter IV (KIV) and control wild-type mice. Quantitative RT-PCR revealed significant reductions in nicotinic acetylcholine receptor alpha 5 (CHRNA5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor (CHRM5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor (CHRM2) in the frontal cortex of KIV mice compared to wild-type mice. Three-week treatments with fluoxetine, phenelzine, duloxetine, imipramine, or an enriched environment treatment (EET) did not affect the altered expression of these genes except that EET increased CHRNA5 levels only in KIV frontal cortex. EET also increased levels of CHRNA7, CHT, and ChAT, again only in the KIV frontal cortex. The imipramine treatment was most prominent among the four antidepressants; it up-regulated hippocampal CHRM2 and frontal cortex CHRM5 in both genotypes, and frontal cortex CHRNA7 only in KIV mice. To the best of our knowledge, this is the first evidence that BDNF deficiency disturbs expression of CHRNA5, CHRM2, and CHRM5. Our results suggest that promoter IV-BDNF deficiency – which occurs under chronic stress – causes cholinergic dysfunctions via these receptors. EET is effective on CHRNA5, while its compensatory induction of other cholinergic genes or drugs targeting CHRNA5, CHRM2, and CHRM5 may become an alternative strategy to reverse these BDNF-linked cholinergic dysfunctions. Chronic stress and lack of neuronal activity reduces expression of promoter IV-driven BDNF. This study provides novel evidence that BDNF deficiency disturbs mRNA expression of acetylcholine receptors, CHRNA5, CHRM2, and CHRM5. Enriched environment treatment (EET) increases cholinergic genes particularly in the BDNF-deficient frontal cortex. Targeting these receptors may become a new strategy to reverse cholinergic dysfunctions caused by BDNF deficiency.
Datum: 16.08.2017


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


The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system

The amyloid precursor protein (APP) is a type I transmembrane glycoprotein better known for its participation in the physiopathology of Alzheimer disease as the source of the beta amyloid fragment. However, the physiological functions of the full length protein and its proteolytic fragments have remained elusive. APP was first described as a cell-surface receptor; nevertheless, increasing evidence highlighted APP as a cell adhesion molecule. In this review, we will focus on the current knowledge of the physiological role of APP as a cell adhesion molecule and its involvement in key events of neuronal development, such as migration, neurite outgrowth, growth cone pathfinding, and synaptogenesis. Finally, since APP is over-expressed in Down syndrome individuals because of the extra copy of chromosome 21, in the last section of the review, we discuss the potential contribution of APP to the neuronal and synaptic defects described in this genetic condition. Read the Editorial Highlight for this article on page 9. Cover Image for this issue: doi. 10.1111/jnc.13817. We review the current knowledge of the physiological role of the amyloid precursor protein (APP) as a cell adhesion molecule and its involvement in key events of neuronal development, such as migration, neurite outgrowth, growth cone pathfinding, and synaptogenesis. This manuscript we will intend to highlight the participation of APP as a plastic cell adhesion molecule particularly implicated in the functional organization of highly dynamic cellular subdomains such as the growth cone and the dendritic spines. Finally, since APP is encoded in chromosome 21 and is over-expressed in Down syndrome, we will discuss the implications of the dosage imbalance of APP on adhesion function and DS neurodevelopment. Read the Editorial Highlight for this article on page 9.Cover Image for this issue: doi. 10.1111/jnc.13817.
Datum: 15.08.2017


A mobile APP for sharing contacts on your cell

The Review highlighted in this Editorial followed a CAEN Return Home Grant This is an Editorial for a review that Sosa and coworkers present in the current issue of the Journal of Neurochemistry of physiological functions for amyloid precursor protein (APP) at dynamic cellular contact sites such as growth cones, neuronal migration tracts, and synapses. Here, APP physically links the extracellular and intracellular milieus through a multitude of binding partners. From these observations, the authors offer a model of APP as a cell adhesion molecule in the brain, providing a context for understanding its role in Alzheimer's disease and Down syndrome. The Review highlighted in this Editorial followed a CAEN Return Home Grant
Datum: 15.08.2017


Manganese and 1-methyl-4-phenylpyridinium (MPP+) induced neurotoxicity indicate differences in morphological, electrophysiological and genome-wide alterations: Implications for idiopathic Parkinson's disease

Idiopathic Parkinson's disease (iPD) and manganese-induced atypical Parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the PD toxin 1-methyl-4-phenylpyridinium ion (MPP+) and manganese (Mn) followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP+ and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~93%) with slow discharge rates (0-5Hz). While MPP+ exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP+ and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the JAK-STAT pathway. We conclude that iPD and atypical Parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. This article is protected by copyright. All rights reserved.
Datum: 12.08.2017


Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism

Histone deacetylase (HDAC) inhibitors prevent neural cell death in in vivo models of cerebral ischaemia, brain injury and neurodegenerative disease. One mechanism by which HDAC inhibitors may do this is by suppressing the excessive inflammatory response of chronically activated microglia. However, the molecular mechanisms underlying this anti-inflammatory effect and the specific HDAC responsible are not fully understood. Recent data from in vivo rodent studies has shown that inhibition of class I HDACs suppresses neuroinflammation and is neuroprotective. In our study we have identified that selective HDAC inhibition with inhibitors apicidin, MS-275 or MI-192, or specific knockdown of HDAC1 or 2 using siRNA, suppresses the expression of cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in BV2 murine microglia activated with lipopolysaccharide (LPS). Furthermore, we found that in the absence of HDAC1, HDAC2 is upregulated and these increased levels are compensatory, suggesting these two HDACs have redundancy in regulating the inflammatory response of microglia. Investigating the possible underlying anti-inflammatory mechanisms suggests an increase in protein expression is not important. Taken together, this study supports the idea that inhibitors selective towards HDAC1 or HDAC2, may be therapeutically useful for targeting neuroinflammation in brain injuries and neurodegenerative disease. This article is protected by copyright. All rights reserved.
Datum: 10.08.2017


Early stage attenuation of phase amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of AD

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 GABAergic signalling. 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) receptors 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 protected by copyright. All rights reserved.
Datum: 04.08.2017


The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C

The frontotemporal lobar degeneration (FTLD) protein progranulin (PGRN) is essential for proper lysosomal function. PGRN localizes in the lysosomal compartment within the cell. Prosaposin (PSAP), the precursor of lysosomal saposin activators (saposin A, B, C, D), physically interacts with PGRN. Previously, we have shown that PGRN and PSAP facilitate each other's lysosomal trafficking. Here, we report that the interaction between PSAP and PGRN requires the linker region of saposin B and C (BC linker). PSAP protein with the BC linker mutated, fails to interact with PGRN and deliver PGRN to lysosomes in the biosynthetic and endocytic pathways. On the other hand, PGRN interacts with PSAP through multiple granulin motifs. Granulin D and E bind to PSAP with similar affinity as full-length PGRN. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14125. The frontotemporal lobar degeneration (FTLD) protein progranulin (PGRN) is essential for proper lysosomal function. Prosaposin (PSAP), the precursor of lysosomal saposin activators (saposin A, B, C, D), physically interacts with PGRN. Here, we show that PGRN and prosaposin PSAP interact through the BC linker of PSAP and granulin motifs (primarily, granulin D and E) to regulate each other's trafficking and function. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14125.
Datum: 04.08.2017


Another piece in the progranulin puzzle: special binding between progranulin and prosaposin creates additional lysosomal access

Loss-of-function mutations in the gene encoding the growth factor progranulin cause degeneration of the ageing brain in a dose-dependent manner. While heterozygous mutations result in adult onset frontotemporal dementia, the much rarer homozygous null mutations cause an early onset lysosomal storage disorder. A better understanding of the biology of progranulin in the central nervous system is needed to find solutions for these incurable diseases. This Editorial highlights a study by Zhou et al. in the current issue of the Journal of Neurochemistry, in which the authors provide data that are a step towards this goal. Progranulin is mainly expressed by neurons and microglia and, although it is a secreted protein, it also ends up in lysosomes. Recently, the trafficking of progranulin and the molecular players involved have become better understood. A special interaction between progranulin and its travelling companion, prosaposin, explains how both proteins can use each other's transport receptors to gain access to lysosomes. This Editorial highlights a study by Hu and colleagues in the current issue of the Journal of Neurochemistry. Recently, the trafficking of progranulin (PGRN) and the molecular players involved have become better understood. A special interaction between PGRN and its traveling companion, prosaposin (PSAP), explains how both proteins can use each other's transport receptors to gain access to lysosomes. PGRN and PSAP are secreted proteins. Direct interaction between PGRN and sortilin (SORT1), and between PSAP and low density lipoprotein receptor-related protein 1 (LRP1) or mannose 6 phosphate receptor (M6PR) results in endocytosis and lysosomal delivery of the ligands. Because both ligands interact, they can indirectly use each other's transport system.
Datum: 04.08.2017


Re-imagining Alzheimer's disease – the diminishing importance of amyloid and a glimpse of what lies ahead

Many have criticized the amyloid cascade hypothesis of Alzheimer's disease for its inconsistencies and failures to either accurately predict disease symptoms or guide the development of productive therapies. In addition to criticisms, however, we believe that the field would benefit from having alternative narratives and disease models that can either replace or function alongside of an amyloid-centric view of Alzheimer's. This review is an attempt to meet that need. We offer three experimentally verified amyloid-independent mechanisms, each of which plausibly contributes substantially to the aetiology of Alzheimer's disease: loss of DNA integrity, faulty cell cycle regulation, regression of myelination. We outline the ways in which the failure of each can contribute to AD initiation and progression, and review how, acting alone or in combination with each other, they are sufficient for explaining the full range of AD pathologies. Yet, these three alternatives represent only a few of the many non-amyloid mechanisms that can explain AD pathogenesis. Therefore instead of proposing a single ‘alternative hypothesis’ to the amyloid cascade theory, sporadic AD is pictured as the result of independent yet intersecting age-related pathologies that afflict the ageing human brain. This article is part of the series “Beyond Amyloid”. The Alzheimer's field can seem like the blind men of the legend trying to describe an elephant by the first part they touch. The amyloid plaque has been inevitably the first part recognized by the newcomers to the Alzheimer's field. Nevertheless, looking at the longitudinal changes of the human brain, there are other age-associated pathologies prior to amyloid depositions that can equally cause age-related dementia. Indeed, a more holistic approach is needed to understand Alzheimer's. Here we offer three possibilities, namely DNA damage, cell cycle dysregulation and myelin degradation, as the examples of how amyloid-independent mechanisms could cause age-associated dementia. This article is part of the series “Beyond Amyloid”.
Datum: 21.06.2017


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 the glyceronephosphate O-acyltransferase knockout (Gnpat KO) mouse 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. Postsynaptically, 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, whereas evoked potentials were unaltered in Gnpat KO mice, ether lipid deficiency leads to fewer spontaneous synaptic vesicle fusion events but, conversely, an increased postsynaptic 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. This article is protected by copyright. All rights reserved.
Datum: 29.05.2017


Is sporadic Alzheimer′s disease a developmental disorder?

Alzheimer′s disease (AD) is a neurodegenerative disorder of higher age that specifically occurs in human. Its clinical phase, characterized by a decline in physiological, psychological, and social functioning, is preceded by a long clinically silent phase of at least several decades that might perhaps even start very early in life. Overall, key functional abilities in AD patients decline in reverse order of the development of these abilities during normal childhood and adolescence. Early symptoms of AD, thus, typically affect mental functions that have been acquired only during very recent hominid evolution and as such are specific to human. Neurofibrillar degeneration, a typical neuropathological lesion of the disease and one of the most robust pathological correlates of cognitive impairment, is rarely seen in non-primate mammals and even non-human primates hardly develop a pathology comparable to those seen in AD patients. Neurofibrillar degeneration is not randomly distributed throughout the AD brain. It preferentially affects brain areas that become increasingly predominant during the evolutionary process of encephalization. During progression of the disease, it affects cortical areas in a stereotypic sequence that inversely recapitulates ontogenetic brain development. The specific distribution of cortical pathology in AD, moreover, appears to be determined by the modular organization of the cerebral cortex which basically is a structural reflection of its ontogeny. Here, we summarize recent evidence that phylogenetic and ontogenetic dimensions of brain structure and function provide the key to our understanding of AD. More recent molecular biological studies of the potential pathogenetic role of a genomic mosaic in the brains of patients with AD might even provide arguments for a developmental origin of AD. This article is part of a series “Beyond Amyloid”. Alzheimer′s disease (AD) is a neurodegenerative disorder of higher age that specifically occurs in human. Here, we summarize recent evidence, that the evolutionary and developmental dimensions of brain structure and function provide the key to our understanding of AD. This article is part of a series “Beyond Amyloid”.
Datum: 29.05.2017


Brain aging and neurodegeneration: from a mitochondrial point of view

Aging is defined as a progressive time-related accumulation of changes responsible for or at least involved in the increased susceptibility to disease and death. The brain seems to be particularly sensitive to the aging process since the appearance of neurodegenerative diseases, including Alzheimer's disease, is exponential with the increasing age. Mitochondria were placed at the center of the ‘free-radical theory of aging’, because these paramount organelles are not only the main producers of energy in the cells, but also to main source of reactive oxygen species. Thus, in this review, we aim to look at brain aging processes from a mitochondrial point of view by asking: (i) What happens to brain mitochondrial bioenergetics and dynamics during aging? (ii) Why is the brain so sensitive to the age-related mitochondrial impairments? (iii) Is there a sex difference in the age-induced mitochondrial dysfunction? Understanding mitochondrial physiology in the context of brain aging may help identify therapeutic targets against neurodegeneration. This article is part of a series “Beyond Amyloid”. We aim to look at brain aging processes from a “mitocentric” point of view by asking: What happens to brain mitochondrial bioenergetics / dynamics during aging? Why are neurons so sensitive to the age-related mitochondrial impairments? Are there sex differences in the age-induced mitochondrial dysfunction? A better understanding of mitochondrial physiology may help identify therapeutic targets against neurodegeneration. This article is part of a series “Beyond Amyloid”.
Datum: 15.05.2017


Microtubule dynamics and the neurodegenerative triad of Alzheimer's disease: The hidden connection

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is, on a histopathological level, characterized by the presence of extracellular amyloid plaques composed of the protein fragment Aβ, and intracellular neurofibrillary tangles, which contain the microtubule-associated protein tau in a hyperphosphorylated state. In AD defects in microtubule (MT) assembly and organization have also been reported; however, it is unclear whether MT abnormalities have a causal and early role in the disease process or represent a common end point downstream of the neurodegenerative cascade. Recent evidence indicates that microtubule-stabilizing drugs prevent axonopathy in animal models of tauopathies and reverse Aβ-induced loss of synaptic connectivity in an ex vivo model of amyloidosis. This could suggest that MT dysfunction connects some of the degenerative events and provides a useful target to simultaneously prevent several neurodegenerative processes in AD. Here, we describe how changes in the structure and dynamics of MTs are involved in the different aspects of the neurodegenerative triad of AD. We discuss evidence that MTs are affected both by tau-dependent and tau-independent mechanisms but appear to be regulated in a distinct way in different neuronal compartments. We argue that modulation of MT dynamics could be of potential benefit but needs to be precisely controlled in a cell and compartment-specific manner to avoid harmful side effects. This article is part of the series “Beyond Amyloid”. Microtubule abnormalities are a common feature in several neurodegenerative diseases. Here, we describe how changes in microtubule dynamics are involved in the different aspects of the neurodegenerative triad of Alzheimer's disease. We discuss evidence that microtubule dynamics is (mis)regulated in a distinct manner in different neuronal compartments. Modulation of microtubule dynamics could be of potential benefit, but needs to be precisely controlled in a cell and compartment-specific manner to avoid harmful side effects. This article is part of the series “Beyond Amyloid”.
Datum: 20.04.2017






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