ASN Neuro[JOURNAL]
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200 papers
Early Cognitive Impairment Behind Nigrostriatal Circuit Neurotoxicity: Are Astrocytes Involved?
Herrera ML, Deza-Ponzio R, Ghersi MS … +6 more , de la Villarmois EA, Virgolini MB, Pérez MF, Molina VA, Bellini MJ, Hereñú CB
ASN Neuro · 2020 · PMID 32466659 · Full text
Cognitive dysfunction is one of the most severe nonmotor symptoms of nigrostriatal impairment. This occurs as a result of profound functional and morphological changes of different neuronal circuits, including modificati...
Cognitive dysfunction is one of the most severe nonmotor symptoms of nigrostriatal impairment. This occurs as a result of profound functional and morphological changes of different neuronal circuits, including modifications in the plasticity and architecture of hippocampal synapses. Such alterations can be implicated in the genesis and progression of dementia associated with neurodegenerative diseases including Parkinson-like symptoms. There are few studies regarding cognitive changes in nigrostriatal animal models. The aim of this study was to characterize the onset of memory deficit after induction of neurotoxicity with 6-hydroxydopamine (6-OHDA) and its correlation with hippocampal dysfunction. For this, we bilaterally microinjected 6-OHDA in dorsolateral Caudate-Putamen unit (CPu) and then, animals were tested weekly for working memory, spatial short-term memory, and motor performance. We evaluated tyrosine hydroxylase (TH) as a dopamine marker, aldehyde dehydrogenase 2 (ALDH2), a mitochondria detoxification enzyme and astrocyte glial fibrillar acid protein (GFAP) an immunoreactivity marker involved in different areas: CPu, substantia nigra, prefrontal cortex, and hippocampus. We observed a specific prefrontal cortex and nigrostriatal pathway TH reduction while ALDH2 showed a decrease-positive area in all the studied regions. Moreover, GFAP showed a specific CPu decrease and hippocampus increase of positively stained area on the third week after toxicity. We also evaluated the threshold to induce long-term potentiation in hippocampal excitability. Our findings showed that reduced hippocampal synaptic transmission was accompanied by deficits in memory processes, without affecting motor performance on the third-week post 6-OHDA administration. Our results suggest that 3 weeks after neurotoxic administration, astrocytes and ALDH2 mitochondrial enzyme modifications participate in altering the properties that negatively affect hippocampal function and consequently cognitive behavior.
Shedding Light on the Dark Side of the Microglia.
St-Pierre MK, Šimončičová E, Bögi E … +1 more , Tremblay MÈ
ASN Neuro · 2020 · PMID 32443939 · Full text
Microglia, the resident immune cells of the central nervous system, are not a homogeneous population; their morphology, molecular profile, and even their ultrastructure greatly vary from one cell to another. Recent advan...
Microglia, the resident immune cells of the central nervous system, are not a homogeneous population; their morphology, molecular profile, and even their ultrastructure greatly vary from one cell to another. Recent advances in the field of neuroimmunology have helped to demystify the enigma that currently surrounds microglial heterogeneity. Indeed, numerous microglial subtypes have been discovered such as the disease-associated microglia, neurodegenerative phenotype, and Cd11c-positive developmental population. Another subtype is the dark microglia (DM), a population defined by its ultrastructural changes associated with cellular stress. Since their first characterization using transmission electron microscopy, they have been identified in numerous disease conditions, from mouse models of Alzheimer's disease, schizophrenia, fractalkine signaling deficiency to chronic stress, just to name a few. A recent study also identified the presence of cells with a similar ultrastructure to the DM in brain samples from schizophrenic patients, underlining the importance of understanding the function of these cells. In this minireview, we aim to summarize the current knowledge on the DM, from their initial ultrastructural characterization to their documentation in various pathological contexts across multiple species. We will also highlight the current limitations surrounding the study of these cells and the future that awaits the DM.
Role of NDEL1 and VEGF/VEGFR-2 in Mouse Hippocampus After Status Epilepticus.
Zhu L, Dai S, Lu D … +6 more , Xu P, Chen L, Han Y, Zhong L, Chang L, Wu Q
ASN Neuro · 2020 · PMID 32423231 · Full text
Nuclear-distribution element-like 1 (NDEL1) is associated with the proliferation and migration of neurons. Vascular endothelial growth factor (VEGF) in combination with VEGF receptor-2 (VEGFR-2) regulates the proliferati...
Nuclear-distribution element-like 1 (NDEL1) is associated with the proliferation and migration of neurons. Vascular endothelial growth factor (VEGF) in combination with VEGF receptor-2 (VEGFR-2) regulates the proliferation and migration of neurons. This study was performed to explore undefined alterations in the expression levels of NDEL1 and VEGF/VEGFR-2 within the hippocampus after status epilepticus (SE). Following the creation of pilocarpine-induced epilepsy models using adolescent male C57BL/6 mice, Western blotting and reverse transcription quantitative polymerase chain reaction were applied to assess the levels of NDEL1, VEGF, and VEGFR-2 expression in whole hippocampi at 1, 2, 3, and 4 weeks post-SE, respectively. Immunofluorescent labeling was also employed to detect the colocalization of NDEL1 and VEGF in the hippocampus. Our results indicated that NDEL1 and VEGF have similar patterns of upregulation throughout the hippocampus. Upregulation of VEGFR-2 occurred only in the early stages, and the expression decreased shortly afterward. NDEL1 and VEGF were coexpressed in the cornu ammonis 3 pyramidal cell, granular, and polymorph layers of the dentate gyrus in the hippocampus. This study revealed that NDEL1, VEGF, and VEGFR-2 may work together and are involved in the pathophysiology in the hippocampus after SE.
Loss of Hippocampal Calretinin and Parvalbumin Interneurons in the 5XFAD Mouse Model of Alzheimer's Disease.
Giesers NK, Wirths O
ASN Neuro · 2020 · PMID 32423230 · Full text
The deposition of amyloid-β peptides in the form of extracellular plaques and neuronal degeneration belong to the hallmark features of Alzheimer's disease (AD). In addition, impaired calcium homeostasis and altered level...
The deposition of amyloid-β peptides in the form of extracellular plaques and neuronal degeneration belong to the hallmark features of Alzheimer's disease (AD). In addition, impaired calcium homeostasis and altered levels in calcium-binding proteins seem to be associated with the disease process. In this study, calretinin- (CR) and parvalbumin- (PV) positive gamma-aminobutyric acid-producing (GABAergic) interneurons were quantified in different hippocampal subfields of 12-month-old wild-type mice, as well as in the transgenic AD mouse models 5XFAD and Tg4-42. While, in comparison with wild-type mice, CR-positive interneurons were mainly reduced in the CA1 and CA2/3 regions in plaque-bearing 5XFAD mice, PV-positive interneurons were reduced in all analyzed subfields including the dentate gyrus. No reduction in CR- and PV-positive interneuron numbers was detected in the non-plaque-forming Tg4-42 mouse, although this model has been previously demonstrated to harbor a massive loss of CA1 pyramidal neurons. These results provide information about hippocampal interneuron numbers in two relevant AD mouse models, suggesting that interneuron loss in this brain region may be related to extracellular amyloid burden.
Diffusion Tensor Imaging Detects Acute and Subacute Changes in Corpus Callosum in Blast-Induced Traumatic Brain Injury.
Venkatasubramanian PN, Keni P, Gastfield R … +9 more , Li L, Aksenov D, Sherman SA, Bailes J, Sindelar B, Finan JD, Lee J, Bailes JE, Wyrwicz AM
ASN Neuro · 2020 · PMID 32403948 · Full text
There is a critical need for understanding the progression of neuropathology in blast-induced traumatic brain injury using valid animal models to develop diagnostic approaches. In the present study, we used diffusion ima...
There is a critical need for understanding the progression of neuropathology in blast-induced traumatic brain injury using valid animal models to develop diagnostic approaches. In the present study, we used diffusion imaging and magnetic resonance (MR) morphometry to characterize axonal injury in white matter structures of the rat brain following a blast applied via blast tube to one side of the brain. Diffusion tensor imaging was performed on acute and subacute phases of pathology from which fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated for corpus callosum (CC), cingulum bundle, and fimbria. Ventricular volume and CC thickness were measured. Blast-injured rats showed temporally varying bilateral changes in diffusion metrics indicating persistent axonal pathology. Diffusion changes in the CC suggested vasogenic edema secondary to axonal injury in the acute phase. Axonal pathology persisted in the subacute phase marked by cytotoxic edema and demyelination which was confirmed by ultrastructural analysis. The evolution of pathology followed a different pattern in the cingulum bundle: axonal injury and demyelination in the acute phase followed by cytotoxic edema in the subacute phase. Spatially, structures close to midline were most affected. Changes in the genu were greater than in the body and splenium; the caudal cingulum bundle was more affected than the rostral cingulum. Thinning of CC and ventriculomegaly were greater only in the acute phase. Our results reveal the persistent nature of blast-induced axonal pathology and suggest that diffusion imaging may have potential for detecting the temporal evolution of blast injury.
Alzheimer Drug Trials: Combination of Safe and Efficacious Biologicals to Break the Amyloidosis-Neuroinflammation Vicious Cycle.
Bartfai T, Lees GV
ASN Neuro · 2020 · PMID 32290675 · Full text
Late-onset Alzheimer’s disease (LOAD) is a long-enduring neurodegenerative disease that progresses for decades before the symptoms of cognitive decline and loss of executive function are measurable. Amyloid deposits amon...
Late-onset Alzheimer’s disease (LOAD) is a long-enduring neurodegenerative disease that progresses for decades before the symptoms of cognitive decline and loss of executive function are measurable. Amyloid deposits among other pathological changes, tau hyperphosphorylation, synapse loss, microglia and astroglia activation, and hippocampal atrophy are among the pathological hallmarks of the disease. These are present in the brain before memory complaints are reported and an AD diagnosis is made. The attempt to postpone or prevent the disease is becoming a more and more plausible goal because new early electrophysiological, cognitive, blood-based, and imaging-based diagnostics are being brought forward at the same time as the first anti-amyloid antibody is about to be approved. In view of known contributions of neuroinflammation to the pathology of LOAD, we should not focus solely on anti-amyloid therapies and ignore the interactive neuroinflammatory component of AD. Our belief is that it would be more rewarding to start clinical trials using combination therapies that are based on approved, safe, and efficacious anti-neuroinflammatory agents such as anti-interleukin-1 signaling agents in combination with the anti-amyloid antibodies that have been shown to be safe in multiyear trials. The proposal is that we should administer these two classes of safe biologicals to symptom-free individuals in midlife who are identified as having a high-risk-for-Alzheimer’s-disease using “precision medicine.”
Unbiased Proteomic Approach Identifies Pathobiological Profiles in the Brains of Preclinical Models of Repetitive Mild Traumatic Brain Injury, Tauopathy, and Amyloidosis.
Ojo JO, Crynen G, Algamal M … +6 more , Vallabhaneni P, Leary P, Mouzon B, Reed JM, Mullan M, Crawford F
ASN Neuro · 2020 · PMID 32241177 · Full text
No concerted investigation has been conducted to explore overlapping and distinct pathobiological mechanisms between repetitive mild traumatic brain injury (r-mTBI) and tau/amyloid proteinopathies considering the long hi...
No concerted investigation has been conducted to explore overlapping and distinct pathobiological mechanisms between repetitive mild traumatic brain injury (r-mTBI) and tau/amyloid proteinopathies considering the long history of association between TBI and Alzheimer’s disease. We address this problem by using unbiased proteomic approaches to generate detailed time-dependent brain molecular profiles of response to repetitive mTBI in C57BL/6 mice and in mouse models of amyloidosis (with amyloid precursor protein KM670/671NL (Swedish) and Presenilin 1 M146L mutations [PSAPP]) and tauopathy (hTau). Brain tissues from animals were collected at different timepoints after injuries (24 hr–12 months post-injury) and at different ages for tau or amyloid transgenic models (3, 9, and 15 months old), encompassing the pre-, peri-, and post-“onset” of cognitive and pathological phenotypes. We identified 30 hippocampal and 47 cortical proteins that were significantly modulated over time in the r-mTBI compared with sham mice. These proteins identified TBI-dependent modulation of phosphatidylinositol-3-kinase/AKT signaling, protein kinase A signaling, and PPARα/RXRα activation in the hippocampus and protein kinase A signaling, gonadotropin-releasing hormone signaling, and B cell receptor signaling in the cortex. Previously published neuropathological studies of our mTBI model showed a lack of amyloid and tau pathology. In PSAPP mice, we identified 19 proteins significantly changing in the cortex and only 7 proteins in hTau mice versus wild-type littermates. When we explored the overlap between our r-mTBI model and the PSAPP/hTau models, a fairly small coincidental change was observed involving only eight significantly regulated proteins. This work suggests a very distinct TBI neurodegeneration and also that other factors are needed to drive pathologies such as amyloidosis and tauopathy postinjury.
Estrogen Receptor Involvement in Noradrenergic Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neurotransmitter and Stimulus-Specific Glycogen Phosphorylase Enzyme Isoform Expression.
Mahmood ASMH, Napit PR, Ali MH … +1 more , Briski KP
ASN Neuro · 2020 · PMID 32233668 · Full text
Norepinephrine (NE) directly regulates ventromedial hypothalamic nucleus (VMN) glucoregulatory neurons and also controls glycogen-derived fuel provision to those cells. VMN nitric oxide (NO) and γ-aminobutyric acid (GABA...
Norepinephrine (NE) directly regulates ventromedial hypothalamic nucleus (VMN) glucoregulatory neurons and also controls glycogen-derived fuel provision to those cells. VMN nitric oxide (NO) and γ-aminobutyric acid (GABA) neurons and astrocytes express estrogen receptor-alpha (ERα) and ER-beta (ERβ) proteins. Current research used selective ERα (1,3(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride) or ERβ (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol) antagonists to address the premise that these ERs govern basal and/or NE-associated patterns of VMN metabolic neuron signaling and astrocyte glycogen metabolism. Both ERs stimulate expression of the enzyme marker protein neuronal nitric oxide synthase, not glutamate decarboxylase. NE inhibition or augmentation of neuronal nitric oxide synthase and glutamate decarboxylase profiles was ER-independent or -dependent, respectively. In both neuron types, VMN ERβ activity inhibited baseline alpha1- (α-) and/or alpha2- (α-)adrenergic receptor (AR) expression, but ERα and -β signaling was paradoxically crucial for noradrenergic upregulation of α-AR. NE inhibited glycogen synthase expression and exerted opposite effects on VMN adenosine monophosphate-sensitive glycogen phosphorylase (GP)-brain type (stimulatory) versus NE-sensitive GP muscle (inhibitory) via ERα or -β activity. Results document unique ERα and ERβ actions on metabolic transmitter and AR protein expression in VMN nitrergic versus GABAergic neurons. ER effects varied in the presence versus absence of NE, indicating that both neuron types are substrates for estradiol and noradrenergic regulatory interaction. NE-dependent ER control of VMN GP variant expression implies that these signals also act on astrocytes to direct physiological stimulus-specific control of glycogen metabolism, which may in turn influence GABA transmission.
VISSA-PLS-DA-Based Metabolomics Reveals a Multitargeted Mechanism of Traditional Chinese Medicine for Traumatic Brain Injury.
Xia Z, Liu W, Zheng F … +7 more , Huang W, Xing Z, Peng W, Tang T, Luo J, Yi L, Wang Y
ASN Neuro · 2020 · PMID 32146828 · Full text
Metabolomics is an emerging tool to uncover the complex pathogenesis of disease, as well as the multitargets of traditional Chinese medicines, with chemometric analysis being a key step. However, conventional algorithms...
Metabolomics is an emerging tool to uncover the complex pathogenesis of disease, as well as the multitargets of traditional Chinese medicines, with chemometric analysis being a key step. However, conventional algorithms are not suitable for directly analyzing data at all times. The variable iterative space shrinkage approach-partial least squares-discriminant analysis, a novel algorithm for data mining, was first explored to screen metabolic varieties to reveal the multitargets of Xuefu Zhuyu decoction (XFZY) against traumatic brain injury (TBI) by the 7th day. Rat plasma from Sham, Vehicle, and XFZY groups was used for gas chromatography/mass spectrometry-based metabolomics. This method showed an improved discrimination ability (area under the curve = 93.64%). Threonine, -4-hydroxyproline, and creatinine were identified as the direct metabolic targets of XFZY against TBI. Five metabolic pathways affected by XFZY in TBI rats, were enriched using Metabolic Pathway Analysis web tool (i.e., phenylalanine, tyrosine, and tryptophan biosynthesis; phenylalanine metabolism; galactose metabolism; alanine, aspartate, and glutamate metabolism; and tryptophan metabolism). In conclusion, metabolomics coupled with variable iterative space shrinkage approach-partial least squares-discriminant analysis model may be a valuable tool for identifying the holistic molecular mechanisms involved in the effects of traditional Chinese medicine, such as XFZY.
Spatiotemporal Distribution of Microglia After Traumatic Brain Injury in Male Mice.
Caplan HW, Cardenas F, Gudenkauf F … +4 more , Zelnick P, Xue H, Cox CS, Bedi SS
ASN Neuro · 2020 · PMID 32146827 · Full text
Traumatic brain injury (TBI) disrupts the complex arrangement of glia and neuronal cells in the central nervous system. Microglia, the resident immune cells, survey the cellular milieu under homeostatic conditions and pl...
Traumatic brain injury (TBI) disrupts the complex arrangement of glia and neuronal cells in the central nervous system. Microglia, the resident immune cells, survey the cellular milieu under homeostatic conditions and play a neuroprotective role via clearance of dead cells and debris such as axons and myelin. Resting (ramified) microglia possess a distinct morphology—small rod-shaped somata with thin processes. After TBI, microglia are activated and transition into an amoeboid morphology. To delineate the spatiotemporal morphological response of microglia after TBI, we used a controlled cortical impact injury model to quantify and characterize microglia at 24 hr and 28 days after TBI in the hippocampus (H) and lateral posterior nucleus of the thalamus (LPNT). Increased numbers of microglia were observed in the H and LPNT at 28 days after controlled cortical impact, but not at 24 hr in comparison to controls. Spatially, controlled cortical impact resulted in an increase of amoeboid microglia bilaterally at 24 hr and 28 days in H and ipsilaterally in LPNT. Temporally, at 28 days, TBI resulted in a significant increase in the number of amoeboid microglia in both H and LPNT. In addition, at 28 days after injury, we observed an increase in translocator protein, a marker for activated microglia, in the ipsilateral thalamus only. TBI results in a spatiotemporal increase in amoeboid microglia in the hippocampus and the LPNT over 28 days. Delineating their spatiotemporal phenotype is critical because it can help identify therapeutic targets with appropriate therapy.
NRF2 as a Therapeutic Target in Neurodegenerative Diseases.
Brandes MS, Gray NE
ASN Neuro · 2020 · PMID 31964153 · Full text
Increased reactive oxygen species production and oxidative stress have been implicated in the pathogenesis of numerous neurodegenerative conditions including among others Alzheimer’s disease, Parkinson’s disease, Hunting...
Increased reactive oxygen species production and oxidative stress have been implicated in the pathogenesis of numerous neurodegenerative conditions including among others Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Friedrich’s ataxia, multiple sclerosis, and stroke. The endogenous antioxidant response pathway protects cells from oxidative stress by increasing the expression of cytoprotective enzymes and is regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). In addition to regulating the expression of antioxidant genes, NRF2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. This is because mitochondrial dysfunction and neuroinflammation are features of many neurodegenerative diseases as well NRF2 has emerged as a promising therapeutic target. Here, we review evidence for a beneficial role of NRF2 in neurodegenerative conditions and the potential of specific NRF2 activators as therapeutic agents.
Physical Activity and Cognitive Function in Mild Cognitive Impairment.
Chang YT
ASN Neuro · 2020 · PMID 31948261 · Full text
Physical exercise has been associated with enhanced memory formation and consolidation in patients with mild cognitive impairment (MCI). This study aimed to investigate the relationship between objective neuropsychologic...
Physical exercise has been associated with enhanced memory formation and consolidation in patients with mild cognitive impairment (MCI). This study aimed to investigate the relationship between objective neuropsychological performances and continuously recorded physical activity. A cut-off value of measured physical activity was used to differentiate early-stage and late-stage MCI. Fifty-four patients with MCI were included. The relationship between cognitive function and measures of daily activity measured by continuous three-axis accelerometers in Xiaomi Mi Band, including subject-level average step counts, average distance (kilometers), and average calorie expenditure per day of 7-day activity, was determined. The slope of the receiver operating characteristic curve was used to determine the measures of activity to draw comparisons between early-stage MCI and late-stage MCI. The patients were assessed by using several cognitive tests such as Cognitive Abilities Screening Instrument and Chinese Version Verbal Learning Test. The multivariate linear regression model indicated a significant correlation of higher average step counts per day of 7-day activity (aver-step-counts) with higher score in visual construction (β = 0.355; =.015). To differentiate patients with late-stage MCI from those with early-stage MCI, the cut-off value of 6,284 steps on aver-step-counts showed an optimal sensitivity and specificity (Youden index = 0.36, area under the curve = 0.651, =.042). The aver-step-counts showed a significantly better differentiating rate between patients with early-stage and late-stage MCI than average calorie expenditure per day of 7-day activity did (=.046). Accelerometer-determined measures of activity patterns show as potential measurement to reflect cognitive function.
Chemotherapeutic Effect of SR9009, a REV-ERB Agonist, on the Human Glioblastoma T98G Cells.
Wagner PM, Monjes NM, Guido ME
ASN Neuro · 2019 · PMID 31825658 · Full text
Glioblastoma multiforme is the most aggressive brain tumor, and human T98G cells constitute a useful glioblastoma multiforme model to evaluate the chemotherapeutic agents. Modern life (shiftwork, jetlag, etc.) may cause...
Glioblastoma multiforme is the most aggressive brain tumor, and human T98G cells constitute a useful glioblastoma multiforme model to evaluate the chemotherapeutic agents. Modern life (shiftwork, jetlag, etc.) may cause circadian disorganization promoting higher cancer risk and metabolic disorders. Although little is known about the tumor-intrinsic circadian clock function, pharmacological modulation of circadian components may offer selective anticancer strategies. REV-ERBs are heme-binding circadian clock components acting as repressors of processes involved in tumorigenesis such as metabolism, proliferation, and inflammation. A synthetic pyrrole derivative (SR9009) that acts as REV-ERBs-specific agonists exhibits potent activity on metabolism and tumor cell viability. Here, we investigated SR9009 effects on T98G cell viability, differential chemotherapy time responses, and underlying metabolic processes (reactive oxygen species [ROS] and lipid droplets [LDs]) and compared it with the proteasome inhibitor Bortezomib treatment. SR9009-treated cells exhibited significant reduction in cell viability with consequences on cell cycle progression. Dexamethasone synchronized cells displayed differential time responses to SR9009 treatment with highest responses 18 to 30 h after synchronization. SR9009 treatment decreased ROS levels while Bortezomib increased them. However, both treatments significantly increased LD levels, whereas the combined treatment showed additive or synergistic effects between both drugs. In addition, we extended these studies to HepG2 cells which also showed a significant decrease in cell viability and ROS levels and the increase in LD levels after SR9009 treatment. Our results suggest that the pharmacological modulation of the tumor-intrinsic clock by REV-ERB agonists severely affects cell metabolism and promotes cytotoxic effects on cancer cells.
Physical Activity Ameliorates Impaired Hippocampal Neurogenesis in the Tg4-42 Mouse Model of Alzheimer's Disease.
Gerberding AL, Zampar S, Stazi M … +2 more , Liebetanz D, Wirths O
ASN Neuro · 2019 · PMID 31818124 · Full text
There is growing evidence from epidemiological studies that especially midlife physical activity might exert a positive influence on the risk and progression of Alzheimer’s disease. In this study, the Tg4-42 mouse model...
There is growing evidence from epidemiological studies that especially midlife physical activity might exert a positive influence on the risk and progression of Alzheimer’s disease. In this study, the Tg4-42 mouse model of Alzheimer’s disease has been utilized to assess the effect of different housing conditions on structural changes in the hippocampus. Focusing on the dentate gyrus, we demonstrate that 6-month-old Tg4-42 mice have a reduced number of newborn neurons in comparison to age-matched wild-type mice. Housing these mice for 4 months with either unlimited or intermittent access to a running wheel resulted in a significant rescue of dentate gyrus neurogenesis. Although neither dentate gyrus volume nor neuron number could be modified in this Alzheimer’s disease mouse model, unrestricted access to a running wheel significantly increased dentate gyrus volume and granule cell number in wild-type mice.
Abnormalities in the Motor Unit of a Fast-Twitch Lower Limb Skeletal Muscle in Huntington's Disease.
Valadão PAC, de Aragão BC, Andrade JN … +14 more , Magalhães-Gomes MPS, Foureaux G, Joviano-Santos JV, Nogueira JC, Machado TCG, de Jesus ICG, Nogueira JM, de Paula RS, Peixoto L, Ribeiro FM, Tapia JC, Jorge ÉC, Guatimosim S, Guatimosim C
ASN Neuro · 2019 · PMID 31818120 · Full text
Huntington’s disease (HD) is a disorder characterized by chronic involuntary movements, dementia, and psychiatric symptoms. It is caused by a mutation in the gene that encodes for huntingtin protein (HTT), leading to the...
Huntington’s disease (HD) is a disorder characterized by chronic involuntary movements, dementia, and psychiatric symptoms. It is caused by a mutation in the gene that encodes for huntingtin protein (HTT), leading to the formation of mutant proteins expressed in various tissues. Although brain pathology has become the hallmark for HD, recent studies suggest that damage of peripheral structures also contributes to HD progression. We previously identified severe alterations in the motor units that innervate cervical muscles in 12-month-old BACHD (Bacterial Artificial Chromosome Huntington’s Disease) mice, a well-established mouse model for HD. Here, we studied lumbar motoneurons and their projections onto hind limb fast-twitch skeletal muscles (tibialis anterior), which control balance and gait in HD patients. We found that lumbar motoneurons were altered in the HD mouse model; the number and size of lumbar motoneurons were reduced in BACHD. Structural alterations were also present in the sciatic nerve and neuromuscular junctions. Acetylcholine receptors were organized in several small patches (acetylcholine receptor fragmentation), many of which were partially innervated. In BACHD mice, we observed atrophy of tibialis anterior muscles, decreased expression of glycolytic fast Type IIB fibers, and at the ultrastructural level, alterations of sarcomeres and mitochondria. Corroborating all these findings, BACHD animals performed worse on motor behavior tests. Our results provide additional evidences that nerve–muscle communication is impaired in HD and that motoneurons from distinct spinal cord locations are similarly affected in the disease.
Neuronal Conditional Knockout of Collapsin Response Mediator Protein 2 Ameliorates Disease Severity in a Mouse Model of Multiple Sclerosis.
Moutal A, Kalinin S, Kowal K … +8 more , Marangoni N, Dupree J, Lin SX, Lis K, Lisi L, Hensley K, Khanna R, Feinstein DL
ASN Neuro · 2019 · PMID 31795726 · Full text
We previously showed that treatment with lanthionine ketimine ethyl ester (LKE) reduced disease severity and axonal damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis and incre...
We previously showed that treatment with lanthionine ketimine ethyl ester (LKE) reduced disease severity and axonal damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis and increased neuronal maturation and survival . A major target of LKE is collapsin response mediator protein 2 (CRMP2), suggesting this protein may mediate LKE actions. We now show that conditional knockout of CRMP2 from neurons using a CamK2a promoter to drive Cre recombinase expression reduces disease severity in the myelin oligodendrocyte glycoprotein (MOG) EAE model, associated with decreased spinal cord axonal damage, and less glial activation in the cerebellum, but not the spinal cord. Immunohistochemical staining and quantitative polymerase chain reaction show CRMP2 depletion from descending motor neurons in the motor cortex, but not from spinal cord neurons, suggesting that the benefits of CRMP2 depletion on EAE may stem from effects on upper motor neurons. In addition, mice in which CRMP2 S522 phosphorylation was prevented by substitution for an alanine residue also showed reduced EAE severity. These results show that modification of CRMP2 expression and phosphorylation can influence the course of EAE and suggests that treatment with CRMP2 modulators such as LKE act in part by reducing CRMP2 S522 phosphorylation.
Intracerebroventricular Infusion of Gangliosides Augments the Adult Neural Stem Cell Pool in Mouse Brain.
Itokazu Y, Li D, Yu RK
ASN Neuro · 2019 · PMID 31635474 · Full text
We previously reported that ganglioside GD3 is the predominant species in neural stem cells (NSCs) and reduced postnatal NSC pools are observed in both the subventricular zone and dentate gyrus (DG) of GD3-synthase knock...
We previously reported that ganglioside GD3 is the predominant species in neural stem cells (NSCs) and reduced postnatal NSC pools are observed in both the subventricular zone and dentate gyrus (DG) of GD3-synthase knockout (GD3S-KO) mouse brains. Specifically, deficiency of GD3 in GD3S-KO animals revealed a dramatic reduction in cellularity in the DG of the hippocampus of the developing mouse brain, resulting in severe behavioral deficits in these animals. To further evaluate the functional role of GD3 in postnatal brain, we performed rescue experiments by intracerebroventricular infusion of ganglioside GD3 in adult GD3S-KO animals and found that it could restore the NSC pools and enhance the NSCs for self-renewal. Furthermore, 5xFAD mouse model was utilized, and GD3 restored NSC numbers and GM1 promoted neuronal differentiation. Our results thus demonstrate that exogenously administered gangliosides are capable to restore the function of postnatal NSCs. Since ganglioside expression profiles are associated not only with normal brain development but also with pathogenic mechanisms of diseases, such as Alzheimer’s disease, we anticipate that the administration of exogenous gangliosides, such as GD3 and GM1, may represent a novel and effective strategy for promoting adult neurogenesis in damaged brain for disease treatment.
Erythropoietin as a Neuroprotective Molecule: An Overview of Its Therapeutic Potential in Neurodegenerative Diseases.
Rey F, Balsari A, Giallongo T … +4 more , Ottolenghi S, Di Giulio AM, Samaja M, Carelli S
ASN Neuro · 2019 · PMID 31450955 · Full text
Erythropoietin (EPO) is a cytokine mainly induced in hypoxia conditions. Its major production site is the kidney. EPO primarily acts on the erythroid progenitor cells in the bone marrow. More and more studies are highlig...
Erythropoietin (EPO) is a cytokine mainly induced in hypoxia conditions. Its major production site is the kidney. EPO primarily acts on the erythroid progenitor cells in the bone marrow. More and more studies are highlighting its secondary functions, with a crucial focus on its role in the central nervous system. Here, EPO may interact with up to four distinct isoforms of its receptor (erythropoietin receptor [EPOR]), activating different signaling cascades with roles in neuroprotection and neurogenesis. Indeed, the EPO/EPOR axis has been widely studied in the neurodegenerative diseases field. Its potential therapeutic effects have been evaluated in multiple disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, as well as brain ischemia, hypoxia, and hyperoxia. EPO is showing great promise by counteracting secondary neuroinflammatory processes, reactive oxygen species imbalance, and cell death in these diseases. Multiple studies have been performed both and , characterizing the mechanisms through which EPO exerts its neurotrophic action. In some cases, clinical trials involving EPO have been performed, highlighting its therapeutic potential. Together, all these works indicate the potential beneficial effects of EPO.
Blood Flow Deficits and Cerebrovascular Changes in a Dietary Model of Hyperhomocysteinemia.
Braun DJ, Abner E, Bakshi V … +8 more , Goulding DS, Grau EM, Lin AL, Norris CM, Sudduth TL, Webster SJ, Wilcock DM, Van Eldik LJ
ASN Neuro · 2019 · PMID 31362539 · Full text
Elevated homocysteine in the blood, or hyperhomocysteinemia, is a recognized risk factor for multiple causes of dementia including Alzheimer’s disease. While reduction of homocysteine levels can generally be accomplished...
Elevated homocysteine in the blood, or hyperhomocysteinemia, is a recognized risk factor for multiple causes of dementia including Alzheimer’s disease. While reduction of homocysteine levels can generally be accomplished in a straightforward manner, the evidence regarding the cognitive benefits of this approach is less clear. To identify adjunct therapeutic targets that might more effectively restore cognition, the present series of experiments characterizes early and later cerebrovascular changes in a model of hyperhomocysteinemia. Sex-balanced groups of adult C57BL/6J mice were administered a diet deficient in vitamins B, B, and B (folate) and supplemented with excess methionine. They were subsequently assessed for changes in cerebral blood flow, memory, blood–brain barrier permeability, and selected vascular-associated genes. Blood flow deficits and barrier permeability changes occurred alongside changes in memory and in genes associated with metabolism, endothelial nitric oxide signaling, barrier integrity, and extracellular matrix remodeling. Significant sexually dimorphic responses to the diet were also detected. Taken together, these data deepen our understanding of a major contributor to dementia burden.
2019 Academic Annual Meeting and the Frontier Seminar on "Glial Cell Function and Disease" (Nantong, China).
Wang YF, Gao YJ
ASN Neuro · 2019 · PMID 31342775 · Full text
The contribution of glial activities to the functions, diseases, and repair of the central nervous system has received increasing attention in neuroscience studies. To promote the research of glial cells and increase coo...
The contribution of glial activities to the functions, diseases, and repair of the central nervous system has received increasing attention in neuroscience studies. To promote the research of glial cells and increase cooperation with peers, the 2019 Academic Annual Meeting and the Frontier Seminar on “Glial Cell Function and Disease” was held in Nantong City, Jiangsu Province, China from May 24 to 26. The meeting was organized by Drs. Yong-Jing Gao and Jia-Wei Zhou of the Chinese Society of Neuroscience Glia Branch. The conference focused on the physiological and pathological functions of astrocytes, microglia, and oligodendrocytes with 25 speakers in two plenary speeches and five sections of more than 180 participants engaged in glial cell research. In the two plenary lectures, Yutian Wang from the University of British Columbia and Xia Zhang from the University of Ottawa presented “Development of NMDAR (N-methyl-D-aspartic acid receptor)-positive allosteric modulators as novel therapeutics for brain disorders” and “Mechanisms underlying cannabinoid regulation of brain function and disease,” respectively. The five sections included microglia and disease, astrocytes and disease, glioma treatment and glial imaging, oligodendrocytes and disease, and glial–neuronal interactions and disease. This meeting allowed extensive and in-depth academic exchanges on the latest research and experimental techniques, represented the highest achievements of Chinese scholars on glial cells, and promoted the cooperation between peers in the fields of glia studies.
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