Biology subjects

Kokovay, E.

Publications and source records attributed to Kokovay, E..

3 recordsLinked to original sources

bioRxiv2025

Age Associated Increase in Microglia Inflammation and Phagocytosis in the Adult Neural Stem Cell Niche.

Adult SVZ neurogenesis declines with age, but the niche mechanisms remain incompletely defined. Here, we show that SVZ microglia acquire activation-associated morphology with aging in male and female C57BL/6 mice. Reanalysis of published SVZ single-cell RNA-Seq data revealed that aged microglia upregulate inflammatory and lysosome/phagosome-related gene programs, including multiple phagocytosis-associated receptors and effectors. Functionally, young SVZ-derived microglia exhibit reduced basal phagocytic activity compared with non-SVZ microglia in vitro, whereas aged SVZ microglia show increased phagocytosis. In vivo SVZ wholemounts reveal increased progenitor-derived material within lysosomal compartments of microglia with age, without an accompanying increase in apoptosis. Inhibiting complement C3 activation partially restores SVZ proliferation in aged mice and coincides with a reduction of progenitor-derived material within lysosomal compartments of aged microglia. These data support a model in which microglial inflammatory signaling and engagement with neural progenitors contributes to age-related suppression of SVZ proliferation. Significance StatementAdult neural stem cells support plasticity and may aid repair after brain injury, but this capacity declines with age. We show that microglia in the aging subventricular zone acquire inflammatory and phagocytic programs, increase their lysosomal association with progenitor-derived material, and are linked to reduced progenitor proliferation. Complement inhibition partially restores proliferative output in aged mice, connecting inflammatory signaling to this niche defect. These findings identify age-dependent microglia-progenitor interactions as a mechanism that may limit neural stem cell activity in the adult brain and suggest immune pathways as possible targets for preserving or restoring neurogenic potential during aging.

cell biology↗

bioRxiv2022

Loss of LRP1 in adult neural stem cells impairs migration to ischemic lesions

After ischemia, cells in the brain parenchyma upregulate stromal derived factor 1 (SDF1), driving chemokine receptor CXCR4-mediated migration of adult neural stem cells from the subventricular zone (SVZ) to the ischemic injury. We discovered a novel regulator of CXCR4 in neural stem cells, low-density lipoprotein receptor related protein 1 (LRP1). We employed a tamoxifen-inducible Nestin-Cre to drive expression of a tdTomato reporter and also knockout floxed LRP1 in adult mice and then subjected mice to middle-cerebral artery occlusion. Examination 2 weeks post-stroke reveals a loss of tdTomato positive cells localizing from the SVZ to the lesion. We show that loss of LRP1 disrupts CXCR4-mediated neural stem cell migration in vitro, which is likely driven by LRP1-mediated loss of CXCR4 expression in vivo. Altogether, our results suggest that LRP1 is a novel regulator of CXCR4 in neural stem cells. Highlights- LRP1 KO in adult neural stem cells disrupts migration to ischemic lesions in vivo. - LRP1 KO in adult neural stem cells disrupts migration towards SDF1 in vitro. - LRP1 positively regulates expression of CXCR4 in adult neural stem cells. eTOC blurbAdult neural stem cells can home to ischemic brain injury and are considered an important part of the repair process after stroke. However, little is known about what molecules help drive this response. The authors discovered that LRP1 is a novel regulator of CXCR4, which is essential for neural stem cell migration to ischemic injury.

neuroscience↗

bioRxiv2021

Microglial CX3CR1I249/M280 variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model

Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 regulates the activation of pathogenic microglia in models of MS and the human polymorphic CX3CR1I249/M280 (hCX3CR1I249/M280) variant increases MS disease progression. However, the role of hCX3CR1I249/M280 on microglial activation and central nervous system repair and regenerative mechanisms remain unknown. Therefore, using transgenic mice expressing the hCX3CR1I249/M280 variant, we aimed to determine the contribution of defective CX3CR1 signaling to remyelination and neurogenesis in the cuprizone model of focal demyelination. Here, we report that mice expressing hCX3CR1I249/M280 exhibit marked demyelination and microgliosis follow acute cuprizone treatment. Cuprizone-treated CX3CR1-deficient and fractalkine-deficient mice displayed a comparable phenotype. Nanostring gene expression analysis in demyelinated lesions showed that hCX3CR1I249/M280 upregulates genes associated with inflammation, oxidative stress and disease-associated microglia. In addition, gene expression analysis in the subgranular zone (SGZ) of the hippocampus in hCX3CR1I249/M280 mice was associated with a significant downregulation of gene networks linked to neurogenesis following acute demyelination. Confocal microscopy showed that hCX3CR1I249/M280 or loss of CX3CR1 signaling inhibits the generation of progeny from the neurogenic niche, including cells involved in myelin repair. These results provide evidence for the pathogenic capacity of hCX3CR1I249/M280 on microglia dysfunction and therapeutic targeting of CX3CR1 to promote CNS repair in MS.

neuroscience↗