1,721,005 research outputs found
Neuropeptide Y modulates hippocampal neurogenesis
No full textEThOS - Electronic Theses Online ServiceGBUnited Kingdo
NPY augments the proliferative effect of FGF2 and increases the expression of FGFR1 on nestin positive postnatal hippocampal precursor cells, via the Y1 receptor
No full textWe have shown that neuropeptide Y (NPY), a peptide neurotransmitter released by hippocampal interneurons, is proliferative for hippocampal neural stem progenitor cells (NSPCs) via the Y1 receptor. Fibroblast growth factor 2 (FGF2), released predominantly by astrocytes, is also a powerful mitogen for postnatal and adult NSPCs, via the FGFR1 receptor. Knockout studies show that NPY and FGF2 are individually necessary, but not sufficient, for seizure-induced neurogenesis, suggesting a possible interaction. Here we examined for interactions between NPY and FGF2 on NSPCs from the postnatal hippocampus and report that the combination of NPY and FGF2 significantly shortens the cell cycle time of nestin positive NSPCs, more than either factor alone. This augmentation of proliferation rate is NPY Y1 receptor mediated, and Y1 receptor activation increases both FGFR1 mRNA and protein in NSPC cultures. NSPCs immunostain for both Y1 and FGFR1 receptors and the interaction is specific for dentate NSPCs.This is the first report of a proliferative factor that augments the proliferative effect of FGF2 and is the first evidence of a positive proliferative interaction between a glial growth factor and a neuronal transmitter, identifying a novel neural activity driven mechanism for modulating the proliferation of hippocampal NSPCs
Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis
No full textGrowing evidence from cerebrospinal fluid samples and post-mortem brain tissue from individuals with multiple sclerosis (MS) and rodent models indicates that the meninges have a key role in the inflammatory and neurodegenerative mechanisms underlying progressive MS pathology. The subarachnoid space and associated perivascular spaces between the membranes of the meninges are the access points for entry of lymphocytes, monocytes and macrophages into the brain parenchyma, and the main route for diffusion of inflammatory and cytotoxic molecules from the cerebrospinal fluid into the brain tissue. In addition, the meningeal spaces act as an exit route for CNS-derived antigens, immune cells and metabolites. A number of studies have demonstrated an association between chronic meningeal inflammation and a more severe clinical course of MS, suggesting that the build-up of immune cell aggregates in the meninges represents a rational target for therapeutic intervention. Therefore, understanding the precise cell and molecular mechanisms, timing and anatomical features involved in the compartmentalization of inflammation within the meningeal spaces in MS is vital. Here, we present a detailed review and discussion of the cellular, molecular and radiological evidence for a role of meningeal inflammation in MS, alongside the clinical and therapeutic implications
Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats
No full textA substantial proportion of cases with secondary progressive multiple sclerosis have extensive inflammation in the leptomeninges that is associated with increased subpial demyelination, neuronal loss and an exacerbated disease course. However, the mechanisms underlying this extensive subpial pathology are poorly understood. We hypothesize that pro-inflammatory cytokine production within the meninges may be a key to this process. Post-mortem cerebrospinal fluid and dissected cerebral leptomeningeal tissue from patients with multiple sclerosis were used to study the presence of tumour necrosis factor and interferon gamma protein and messenger RNA levels. A novel model of subpial cortical grey matter demyelination was set up in Dark Agouti rats and analysed using quantitative immunohistochemistry. Increased expression of the pro-inflammatory cytokines tumour necrosis factor and interferon gamma was found in the meninges of cases with secondary progressive multiple sclerosis exhibiting tertiary lymphoid-like structures. Injection of tumour necrosis factor and interferon gamma into the subarachnoid space of female Dark Agouti rats pre-immunized with a subclinical dose of myelin oligodendrocyte glycoprotein mimicked the pathology seen in multiple sclerosis, including infiltration of lymphocytes (CD4+ and CD8+ T cells and CD79+ B cells) into the meninges and extensive subpial demyelination. Extensive microglial/macrophage activation was present in a gradient from the pial surface to deeper cortical layers. Demyelination did not occur in control animals immunized with incomplete Freund's adjuvant and injected with cytokines. These results support the hypothesis that pro-inflammatory molecules produced in the meninges play a major role in cortical demyelination in multiple sclerosis, but also emphasize the involvement of an anti-myelin immune response
NPY mediates basal and seizure-induced proliferation in the subcallosal zone
No full textStem cell niches exist around the lateral ventricle and in the subgranular layer of the dentate gyrus, supporting adult neurogenesis. Recently, a third germinal layer, the subcallosal zone has been identified supporting the generation of oligodendrocytes in the adult brain. We have previously described a proliferative role for neuropeptide Yon precursors in the dentate gyrus, caudal subventricular zone and subcallosal zone under basal conditions and in the dentate gyrus after seizures. Here we sought to determine a role for neuropeptide Y in seizure-induced proliferation in the subcallosal niche. Using the chemoconvulsant kainate and neuropeptide Y-/- mice with controls, we show an effect of neuropeptide Y on basal proliferation and demonstrate a significant reduction in seizure-induced proliferation in the subcallosal zone
High levels of perivascular inflammation and active demyelinating lesions at time of death associated with rapidly progressive multiple sclerosis disease course:a retrospective post-mortem cohort study
Full text linkObjective: Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones. Methods: In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. Results: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858–0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886–0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. Interpretation: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024.</p
Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology
No full textIntrathecal antibody production is a hallmark of multiple sclerosis and humoral immunity is thought to play an important role in the inflammatory response and development of demyelinated lesions. The presence of lymphoid follicle-like structures in the cerebral meninges of some multiple sclerosis patients indicates that B-cell maturation can be sustained locally within the CNS and contribute to the establishment of a compartmentalized humoral immune response. In this study we examined the distribution of ectopic B-cell follicles in multiple sclerosis cases with primary and secondary progressive clinical courses to determine their association with clinical and neuropathological features. A detailed immunohistochemical and morphometric analysis was performed on post-mortem brain tissue samples from 29 secondary progressive (SP) and 7 primary progressive (PP) multiple sclerosis cases. B-cell follicles were detected in the meninges entering the cerebral sulci of 41.4% of the SPMS cases, but not in PPMS cases. The SPMS cases with follicles significantly differed from those without with respect to a younger age at multiple sclerosis onset, irreversible disability and death and more pronounced demyelination, microglia activation and loss of neurites in the cerebral cortex. Cortical demyelination in these SPMS cases was also more severe than in PPMS cases. Notably, all meningeal B-cell follicles were found adjacent to large subpial cortical lesions, suggesting that soluble factors diffusing from these structures have a pathogenic role. These data support an immunopathogenetic mechanism whereby B-cell follicles developing in the multiple sclerosis meninges exacerbate the detrimental effects of humoral immunity with a subsequent major impact on the integrity of the cortical structures
Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells
No full textNew neurones are produced in the adult hippocampus throughout life and are necessary for certain types of hippocampal learning. Little, however, is known about the control of hippocampal neurogenesis. We used primary hippocampal cultures from early post-natal rats and neuropeptide Y Y1 receptor knockout mice as well as selective neuropeptide Y receptor antagonists and agonists to demonstrate that neuropeptide Y is proliferative for nestin-positive, sphere-forming hippocampal precursor cells and beta-tubulin-positive neuroblasts and that the neuroproliferative effect of neuropeptide Y is mediated via its Y1 receptor. Immunohistochemistry confirmed Y1 receptor staining on both nestin-positive cells and beta-tubulin-positive cells in culture and short pulse 5-bromo-2-deoxyuridine studies demonstrated that neuropeptide Y has a proliferative effect on both cell types. These studies suggest that the proliferation of hippocampal neuroblasts and precursor cells is increased by neuropeptide Y and, therefore, that hippocampal learning and memory may be modulated by neuropeptide Y-releasing interneurones
Detection of Epstein-Barr virus and B-cell follicles in the multiple sclerosis brain: what you find depends on how and where you look
No full textComment on: Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. [Brain. 2009
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