Vaccination reduces central nervous system IL-1ß and memory deficits after COVID-19 in mice.

Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1ß and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1ß during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1ß as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.

Histone Deacetylases 1 and 2 Regulate Microglia Function during Development, Homeostasis, and Neurodegeneration in a Context-Dependent Manner.

Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival. In contrast, Hdac1 and Hdac2 were not required for adult microglia survival during homeostasis. In a mouse model of Alzheimer's disease, deletion of Hdac1 and Hdac2 in microglia, but not in neuroectodermal cells, resulted in a decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a role for epigenetic factors that differentially affect microglia development, homeostasis, and disease that could potentially be utilized therapeutically.

Complement dysregulation in the central nervous system during development and disease.

The complement cascade is an important arm of the immune system that plays a key role in protecting the central nervous system (CNS) from infection. Recently, it has also become clear that complement proteins have fundamental roles in the developing and aging CNS that are distinct from their roles in immunity. During neurodevelopment, complement signalling is involved in diverse processes including neural tube closure, neural progenitor proliferation and differentiation, neuronal migration, and synaptic pruning. In acute neurotrauma and ischamic brain injury, complement drives inflammation and neuronal death, but also neuroprotection and regeneration. In diseases of the aging CNS including dementias and motor neuron disease, chronic complement activation is associated with glial activation, and synapse and neuron loss. Proper regulation of complement is thus essential to allow for an appropriately developed CNS and prevention of excessive damage following neurotrauma or during neurodegeneration. This review provides a comprehensive overview of the evidence for functional roles of complement in brain formation, and its dysregulation during acute and chronic disease. We also provide working models for how complement can lead to neurodevelopmental disorders such as schizophrenia and autism, and either protect, or propagate neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis.

A conformation-specific antibody against oligomeric ß-amyloid restores neuronal integrity in a mouse model of Alzheimer's disease.

Conformationally distinct aggregates of the amyloid ß (Aß) peptide accumulate in brains of patients with Alzheimer's disease (AD), but the roles of the different aggregates in disease progression are not clear. We previously isolated two single-chain variable domain antibody fragments (scFvs), C6T and A4, that selectively bind different toxic conformational variants of oligomeric Aß. Here, we utilize these scFvs to localize the presence of these Aß variants in human AD brain and to demonstrate their potential as therapeutic agents for treating AD. Both A4 and C6T label oligomeric Aß in extracellular amyloid plaques, whereas C6T also labels intracellular oligomeric Aß in human AD brain tissue and in an AD mouse model. For therapeutic studies, the A4 and C6T scFvs were expressed in the AD mice by viral infection of liver cells. The scFvs were administered at 2 months of age, and mice sacrificed at 9 months. The scFvs contained a peptide tag to facilitate transport across the blood brain barrier. While treatment with C6T only slightly decreased Aß deposits and plaque-associated inflammation, it restored neuronal integrity to WT levels, significantly promoted growth of new neurons, and impressively rescued survival rates to WT levels. Treatment with A4 on the other hand significantly decreased Aß deposits but did not significantly decrease neuroinflammation or promote neuronal integrity, neurogenesis, or survival rate. These results suggest that the specific Aß conformation targeted in therapeutic applications greatly affects the outcome, and the location of the targeted Aß variants may also play a critical factor.

Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure.

BACKGROUND: Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis. METHODS: Galantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration). RESULTS: Results indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox). CONCLUSIONS: Collectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

Effects of Platelet-Rich Plasma on Cellular Populations of the Central Nervous System: The Influence of Donor Age.

Platelet-rich plasma (PRP) is a biologic therapy that promotes healing responses across multiple medical fields, including the central nervous system (CNS). The efficacy of this therapy depends on several factors such as the donor's health status and age. This work aims to prove the effect of PRP on cellular models of the CNS, considering the differences between PRP from young and elderly donors. Two different PRP pools were prepared from donors 65‒85 and 20‒25 years old. The cellular and molecular composition of both PRPs were analyzed. Subsequently, the cellular response was evaluated in CNS in vitro models, studying proliferation, neurogenesis, synaptogenesis, and inflammation. While no differences in the cellular composition of PRPs were found, the molecular composition of the Young PRP showed lower levels of inflammatory molecules such as CCL-11, as well as the presence of other factors not found in Aged PRP (GDF-11). Although both PRPs had effects in terms of reducing neural progenitor cell apoptosis, stabilizing neuronal synapses, and decreasing inflammation in the microglia, the effect of the Young PRP was more pronounced. In conclusion, the molecular composition of the PRP, conditioned by the age of the donors, affects the magnitude of the biological response.

A Balancing Act: The Immune System Supports Neurodegeneration and Neurogenesis.

Decapod crustaceans, like mammals, retain the ability to make new neurons throughout life. In mammals, immune cells are closely associated with stem cells that generate adult-born neurons. In crayfish, evidence suggests that immune cells (hemocytes) originating in the immune system travel to neurogenic regions and transform into neural progenitor cells. This nontraditional immune activity takes place continuously under normal physiological conditions, but little is known under pathological conditions (neurodegeneration). In this study, the immune system and its relationship with neurogenesis were investigated during neurodegeneration (unilateral antennular ablation) in adult crayfish. Our experiments show that after ablation (1) Proliferating cells decrease in neurogenic areas of the adult crayfish brain; (2) The immune response, but not neurogenesis, is ablation-side dependent; (3) Inducible nitric oxide synthase (iNOS) plays a crucial role in the neurogenic niche containing neural progenitors during the immune response; (4) Brain areas targeted by antennular projections respond acutely (15 min) to the lesion, increasing the number of local immune cells; (5) Immune cells are recruited to the area surrounding the ipsilateral neurogenic niche; and (6) The vasculature in the niche responds acutely by dilation and possibly also neovascularization. We conclude that immune cells are important in both neurodegeneration and neurogenesis by contributing in physiological conditions to the maintenance of the number of neural precursor cells in the neurogenic niche (neurogenesis), and in pathological conditions (neurodegeneration) by coordinating NO release and vascular responses associated with the neurogenic niche. Our data suggest that neural damage and recovery participate in a balance between these competing immune cell roles.

Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration.

Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells play key roles in maintaining brain homeostasis and regulating brain immune responses. They continuously scan and sense the brain environment to detect any occurring changes. Upon detection of a signal related to physiological or pathological processes, the cells are activated and transform to an amoeboid-like phenotype, mounting adequate responses that range from phagocytosis to secretion of inflammatory and trophic factors. The overwhelming evidence suggests that microglia are crucially implicated in influencing neuronal proliferation and differentiation, as well as synaptic connections, and thereby cognitive and behavioral functions. Here, we review the role of microglia in adult neurogenesis under physiological conditions, and how this role is affected in neurodegenerative diseases.

Maternal immune activation-induced PPARγ-dependent dysfunction of microglia associated with neurogenic impairment and aberrant postnatal behaviors in offspring.

Maternal infection during pregnancy is an important factor involved in the pathogenesis of brain disorders in the offspring. Mounting evidence from maternal immune activation (MIA) animals indicates that microglial priming may contribute to neurodevelopmental abnormalities in the offspring. Because peroxisome proliferator-activated receptor gamma (PPARγ) activation exerts neuroprotective effects by regulating neuroinflammatory response, it is a pharmacological target for treating neurogenic disorders. We investigated the effect of PPARγ-dependent microglial activation on neurogenesis and consequent behavioral outcomes in male MIA-offspring. Pregnant dams on gestation day 18 received Poly(I:C) (1, 5, or 10 mg/kg; i.p.) or the vehicle. The MIA model that received 10 mg/kg Poly(I:C) showed significantly increased inflammatory responses in the maternal serum and fetal hippocampus, followed by cognitive deficits, which were highly correlated with hippocampal neurogenesis impairment in prepubertal male offspring. The microglial population in hippocampus increased, displayed decreased processes and larger soma, and had a higher expression of the CD11b, which is indicative of the M1 phenotype (classical activation). Activation of the PPARγ pathway by pioglitazone in the MIA offspring rescued the imbalance of the microglial activation and ameliorated the MIA-induced suppressed neurogenesis and cognitive impairments and anxiety behaviors. In an in vitro experiment, PPARγ-induced M2 microglia (alternative activation) promoted the proliferation and differentiation of neural precursor cells. These results indicated that the MIA-induced long-term changes in microglia phenotypes were associated with hippocampal neurogenesis and neurobehavioral abnormalities in offspring. Modulation of the microglial phenotypes was associated with a PPARγ-mediated neuroprotective mechanism in the MIA offspring and may serve as a potential therapeutic approach for prenatal immune activation-induced neuropsychiatric disorders.

Type 2/Th2-driven inflammation impairs olfactory sensory neurogenesis in mouse chronic rhinosinusitis model.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a chronic inflammatory disease often accompanied by impairment of sense of smell. This symptom has been somewhat overlooked, and its relationship to inflammatory cytokines, tissue compression, neuronal loss, and neurogenesis is still unclear. METHODS: In order to elucidate potential mechanisms leading to CRS in humans, we have established a type 2/T helper type 2 cell (Th2)-mediated allergic CRS mouse model, based on house dust mite (HDM) and Staphylococcus aureus enterotoxin B (SEB) sensitization. The inflammatory status of the olfactory epithelium (OE) was assessed using histology, biochemistry, and transcriptomics. The sense of smell was evaluated by studying olfactory behavior and recording electro-olfactograms (EOGs). RESULTS: After 22 weeks, a typical type 2/Th2-mediated inflammatory profile was obtained, as demonstrated by increased interleukin (IL)-4, IL-5, and IL-13 in the OE. The number of mast cells and eosinophils was increased, and infiltration of these cells into the olfactory mucosa was also observed. In parallel, transcriptomic and histology analyses indicated a decreased number of immature olfactory neurons, possibly due to decreased renewal. However, the number of mature sensory neurons was not affected and neither the EOG nor olfactory behavior was impaired. CONCLUSION: Our mouse model of CRS displayed an allergic response to HDM + SEB administration, including the type 2/Th2 inflammatory profile characteristic of human eosinophilic CRSwNP. Although the sense of smell did not appear to be altered in these conditions, the data reveal the influence of chronic inflammation on olfactory neurogenesis, suggesting that factors unique to humans may be involved in CRSwNP-associated anosmia.

JAK2/STAT3 signaling mediates IL-6-inhibited neurogenesis of neural stem cells through DNA demethylation/methylation.

Neuroinflammation, considered as a pathological hallmark of Alzheimer's disease (AD), has been demonstrated to affect hippocampal neurogenesis and cognitive function. Interleukin-6 (IL-6) is a proinflammatory cytokine known to modulate neurogenesis. However, the mechanisms are still largely unknown. Here, we reported that IL-6 suppressed neurogenesis via a JAK2/STAT3 signaling in neural stem cells (NSCs). Importantly, we found that NeuroD1 (Neurogenic differentiation 1) gene expression, which drives NSCs neurodifferentiation, was regulated by TET3 and DNMT1 in a JAK2/STAT3-dependent manner. We further found that JAK2/STAT3 inhibition enhanced demethylation of NeuroD1 regulatory elements in IL-6-treated cells, which is related to the significant upregulation of TET3 expression as well as the decreased expression of DNMT1. Furthermore, Inhibiting JAK2/STAT3 significantly rescued the memory deficits and hippocampal neurogenesis dysfunction in APP/PS1 mice. Our data suggest that JAK2/STAT3 signaling plays a vital role in suppressing neurogenesis of NSCs exposed to IL-6 at the epigenetic level, by regulating DNA methylation/demethylation.

Complement activation sustains neuroinflammation and deteriorates adult neurogenesis and spatial memory impairment in rat hippocampus following sleep deprivation.

BACKGROUND: An association between neuroinflammation, reduced adult neurogenesis, and cognitive impairment has been established in sleep deprivation (SD). Complement receptors are expressed on neuronal and glial cells, thus, regulate the neuroinflammation, neurogenesis and learning/memory. However, understanding of the effect of SD on the brain-immune system interaction associated with cognitive dysfunction and its mechanisms is obscure. We hypothesized that complement activation induced changes in inflammatory and neurogenesis related proteins might be involved in the cognitive impairment during SD. METHODOLOGY: Adult male Sprague Dawley rats were used. Rats were sleep deprived for 48 h using a novel automated SD apparatus. Dosage of BrdU (50 mg/kg/day, i.p. in 0.07 N NaOH), complement C3a receptor antagonist (C3aRA; SB290157; 1 mg/kg/day, i.p.) in 1.16% v/v PBS and complement C5a receptor antagonist (C5aRA; W-54011; 1 mg/kg/day, i.p.) in normal saline were used. Rats were subjected to spatial memory evaluation following SD. Hippocampal tissue was collected for biochemical, molecular, and immunohistochemical studies. T-test and ANOVA were used for the statistical analysis. RESULTS: An up-regulation in the levels of complement components (C3, C5, C3a, C5a) and receptors (C3aR and C5aR) in hippocampus, displayed the complement activation during SD. Selective antagonism of C3aR/C5aR improved the spatial memory performance of sleep-deprived rats. C3aR antagonist (C3aRA) or C5aR antagonist (C5aRA) treatment inhibited the gliosis, maintained inflammatory cytokines balance in hippocampus during SD. Complement C3aR/C5aR antagonism improved hippocampal adult neurogenesis via up-regulating the BDNF level following SD. Administration of C3aRA and C5aRA significantly maintained synaptic homeostasis in hippocampus after SD. Gene expression analysis showed down-regulation in the mRNA levels of signal transduction pathways (Notch and Wnt), differentiation and axogenous proteins, which were found to be improved after C3aRA/C5aRA treatment. These findings were validated at protein and cellular level. Changes in the corticosterone level and ATP-adenosine-NO pathway were established as the key mechanisms underlying complement activation mediated consequences of SD. CONCLUSION: Our study suggests complement (C3a-C3aR and C5a-C5aR) activation as the novel mechanism underlying spatial memory impairment via promoting neuroinflammation and adult neurogenesis decline in hippocampus during SD, thereby, complement (C3aR/C5aR) antagonist may serve as the novel therapeutics to improve the SD mediated consequences.

Distinct Effects of miR-210 Reduction on Neurogenesis: Increased Neuronal Survival of Inflammation But Reduced Proliferation Associated with Mitochondrial Enhancement.

Neurogenesis is essential to brain development and plays a central role in the response to brain injury. Stroke and head trauma stimulate proliferation of endogenous neural stem cells (NSCs); however, the survival of young neurons is sharply reduced by postinjury inflammation. Cellular mitochondria are critical to successful neurogenesis and are a major target of inflammatory injury. Mitochondrial protection was shown to improve survival of young neurons. This study tested whether reducing cellular microRNA-210 (miR-210) would enhance mitochondrial function and improve survival of young murine neurons under inflammatory conditions. Several studies have demonstrated the potential of miR-210 inhibition to enhance and protect mitochondrial function through upregulation of mitochondrial proteins. Here, miR-210 inhibition significantly increased neuronal survival and protected the activity of mitochondrial enzymes cytochrome c oxidase and aconitase in differentiating NSC cultures exposed to inflammatory mediators. Unexpectedly, we found that reducing miR-210 significantly attenuated NSC proliferation upon induction of differentiation. Further investigation revealed that increased mitochondrial function suppressed the shift to primarily glycolytic metabolism and reduced mitochondrial length characteristic of dividing cells. Activation of AMP-regulated protein kinase-retinoblastoma signaling is important in NSC proliferation and the reduction of this activation observed by miR-210 inhibition is one mechanism contributing to the reduced proliferation. Postinjury neurogenesis occurs as a burst of proliferation that peaks in days, followed by migration and differentiation over weeks. Our studies suggest that mitochondrial protective miR-210 inhibition should be delayed until after the initial burst of proliferation, but could be beneficial during the prolonged differentiation stage.SIGNIFICANCE STATEMENT Increasing the success of endogenous neurogenesis after brain injury holds therapeutic promise. Postinjury inflammation markedly reduces newborn neuron survival. This study found that enhancement of mitochondrial function by reducing microRNA-210 (miR-210) levels could improve survival of young neurons under inflammatory conditions. miR-210 inhibition protected the activity of mitochondrial enzymes cytochrome c oxidase and aconitase. Conversely, we observed decreased precursor cell proliferation likely due to suppression of the AMP-regulated protein kinase-retinoblastoma axis with miR-210 inhibition. Therefore, mitochondrial protection is a double-edged sword: early inhibition reduces proliferation, but inhibition later significantly increases neuroblast survival. This explains in part the contradictory published reports of the effects of miR-210 on neurogenesis.

Systemic Neutrophil Depletion Modulates the Migration and Fate of Transplanted Human Neural Stem Cells to Rescue Functional Repair.

The interaction of transplanted stem cells with local cellular and molecular cues in the host CNS microenvironment may affect the potential for repair by therapeutic cell populations. In this regard, spinal cord injury (SCI), Alzheimer's disease, and other neurological injuries and diseases all exhibit dramatic and dynamic changes to the host microenvironment over time. Previously, we reported that delayed transplantation of human CNS-derived neural stem cells (hCNS-SCns) at 9 or 30 d post-SCI (dpi) resulted in extensive donor cell migration, predominantly neuronal and oligodendrocytic donor cell differentiation, and functional locomotor improvements. Here, we report that acute transplantation of hCNS-SCns at 0 dpi resulted in localized astroglial differentiation of donor cells near the lesion epicenter and failure to produce functional improvement in an all-female immunodeficient mouse model. Critically, specific immunodepletion of neutrophils (polymorphonuclear leukocytes) blocked hCNS-SCns astroglial differentiation near the lesion epicenter and rescued the capacity of these cells to restore function. These data represent novel evidence that a host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population, and support targeting the inflammatory microenvironment in combination with cell transplantation after SCI.SIGNIFICANCE STATEMENT The interaction of transplanted cells with local cellular and molecular cues in the host microenvironment is a key variable that may shape the translation of neurotransplantation research to the clinical spinal cord injury (SCI) human population, and few studies have investigated these events. We show that the specific immunodepletion of polymorphonuclear leukocyte neutrophils using anti-Ly6G inhibits donor cell astrogliosis and rescues the capacity of a donor cell population to promote locomotor improvement after SCI. Critically, our data demonstrate novel evidence that a specific host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population.

Recent advances in the understanding of microglial development and homeostasis.

Microglia are the resident macrophages of the central nervous system (CNS). These pivotal cells arise early during embryonic development and provide both developmental support and immune protection to the brain. In adults, microglia contribute to brain homeostasis and mediate an intriguing interplay between the CNS and the gut microbiota. When dysregulated, microglia are also implicated in numerous neurological disorders, and thus fully understanding their regulation and functions will facilitate rational design of therapies to alleviate these conditions; however it remains unclear how the multiple factors modulating microglial activity are integrated at the organism and cellular levels. In this review, we will discuss recent advances in the understanding of microglial regulation and highlight the key questions that remain to be answered around microglial development, homeostasis and functions.

An enriched environment restores hepatitis B vaccination-mediated impairments in synaptic function through IFN-γ/Arginase1 signaling.

Activation of the neonatal immune system may contribute to deficits in neuronal plasticity. We have reported that neonatal vaccination with a hepatitis B vaccine (HBV) transiently impairs mood status and spatial memory involving a systemic T helper (Th) 2 bias and M1 microglial activation. Here, an EE induced microglial anti-inflammatory M2 polarization, as evidenced by selectively enhanced expression of the Arginase1 gene (Arg-1) in the hippocampus. Interestingly, knock-down of the Arg-1 gene prevented the effects of EE on restoring the dendritic spine density. Moreover, levels of the Th1-derived cytokine IFN-gamma (IFN-γ) were elevated in the choroid plexus (CP), which is the interface between the brain and the periphery. IFN-γ-blocking antibodies blunted the protective effects of an EE on spine density and LTP. Furthermore, levels of complement proteins C1q and C3 were elevated, and this elevation was associated with synapse loss induced by the HBV, whereas an EE reversed the effects of the HBV. Similarly, blockade of C1q activation clearly prevented synaptic pruning by microglia, LTP inhibition and memory deficits in hepatitis B-vaccinated mice. Together, the EE-induced increase in IFN-γ levels in the CP may disrupt systemic immunosuppression related to HBV via an IFN-γ/Arg-1/complement-dependent pathway.

In-Depth Cerebrospinal Fluid Quantitative Proteome and Deglycoproteome Analysis: Presenting a Comprehensive Picture of Pathways and Processes Affected by Multiple Sclerosis.

In the current study, we conducted a quantitative in-depth proteome and deglycoproteome analysis of cerebrospinal fluid (CSF) from relapsing-remitting multiple sclerosis (RRMS) and neurological controls using mass spectrometry and pathway analysis. More than 2000 proteins and 1700 deglycopeptides were quantified, with 484 proteins and 180 deglycopeptides significantly changed between pools of RRMS and pools of controls. Approximately 300 of the significantly changed proteins were assigned to various biological processes including inflammation, extracellular matrix organization, cell adhesion, immune response, and neuron development. Ninety-six significantly changed deglycopeptides mapped to proteins that were not found changed in the global protein study. In addition, four mapped to the proteins oligo-myelin glycoprotein and noelin, which were found oppositely changed in the global study. Both are ligands to the nogo receptor, and the glycosylation of these proteins appears to be affected by RRMS. Our study gives the most extensive overview of the RRMS affected processes observed from the CSF proteome to date, and the list of differential proteins will have great value for selection of biomarker candidates for further verification.

Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system.

Neuroscientists are likely to discover new sex differences in the coming years, spurred by the National Institutes of Health initiative to include both sexes in preclinical studies. This review summarizes the current state of knowledge of the cellular and molecular mechanisms underlying sex differences in the mammalian nervous system, based primarily on work in rodents. Cellular mechanisms examined include neurogenesis, migration, the differentiation of neurochemical and morphological cell phenotype, and cell death. At the molecular level we discuss evolving roles for epigenetics, sex chromosome complement, the immune system, and newly identified cell signaling pathways. We review recent findings on the role of the environment, as well as genome-wide studies with some surprising results, causing us to re-think often-used models of sexual differentiation. We end by pointing to future directions, including an increased awareness of the important contributions of tissues outside of the nervous system to sexual differentiation of the brain.

Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation.

BACKGROUND: Sleep deprivation (SD) leads to cognitive impairment. Neuroinflammation could be a significant contributing factor in the same. An increase in regional brain pro-inflammatory cytokines induces cognitive deficits, however, the magnitude of the effect under SD is not apparent. It is plausible that microglia activation could be involved in the SD-induced cognitive impairment by modulation of neuronal cell proliferation, differentiation, and brain-derived neuronal factor (BDNF) level. The present study aimed to evaluate the possible beneficial effect of minocycline in amelioration of spatial memory decline during SD by its anti-inflammatory and neuroprotective actions. We scrutinized the effect of minocycline on the inflammatory cytokine levels associated with glial cells (microglia and astrocytes) activity and neurogenesis markers crucial for behavioral functions during SD. METHODS: Male Sprague-Dawley rats weighing 230-250 g were sleep deprived for 48 h using automated cage shaking apparatus. The spatial memory was tested using MWM apparatus immediately after completion of SD with and without minocycline. The animals were euthanized, blood was collected, and brain was extracted for neuroinflammation and neurogenesis studies. The set of experiments were also conducted with use of temozolomide, a neurogenesis blocker. RESULTS: Minocycline treatment increased the body weight, food intake, and spatial memory performance which declined during SD. It reduced the pro-inflammatory and increased the anti-inflammatory cytokine levels in hippocampus and plasma and inhibited the reactive gliosis in the hippocampus evidenced by improved cell count, morphology, and immunoreactivity. Additionally, minocycline administration promoted neurogenesis at different stages: proliferation (BrdU, Ki-67), differentiation (DCX) cells and growth factor (BDNF). However, no significant change was observed in maturation (NeuN) during SD. In addition, molecules related to behavior, inflammation, and neurogenesis were shown to be more affected after temozolomide administration during SD, and changes were restored with minocycline treatment. We observed a significant correlation of neurogenesis with microglial activation, cytokine levels, and spatial memory during SD. CONCLUSION: The present study demonstrated that the SD-induced decline in spatial memory, neuronal cells proliferation, differentiation, and BDNF level could be attributed to upregulation of neuroinflammatory molecules, and minocycline may be an effective intervention to counteract these changes. Microglial activation is involved in SD-induced changes in inflammatory molecules, neurogenesis, and spatial memory.

Demyelination causes adult CNS progenitors to revert to an immature state and express immune cues that support their migration.

The declining efficiency of myelin regeneration in individuals with multiple sclerosis has stimulated a search for ways by which it might be therapeutically enhanced. Here we have used gene expression profiling on purified murine oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the adult CNS, to obtain a comprehensive picture of how they become activated after demyelination and how this enables them to contribute to remyelination. We find that adult OPCs have a transcriptome more similar to that of oligodendrocytes than to neonatal OPCs, but revert to a neonatal-like transcriptome when activated. Part of the activation response involves increased expression of two genes of the innate immune system, IL1ß and CCL2, which enhance the mobilization of OPCs. Our results add a new dimension to the role of the innate immune system in CNS regeneration, revealing how OPCs themselves contribute to the postinjury inflammatory milieu by producing cytokines that directly enhance their repopulation of areas of demyelination and hence their ability to contribute to remyelination.