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Therapeutic reactivation of hippocampal progenitors reverses cognition decline in progressive brain demyelination

ABSTRACT: Chronic brain demyelination and neurodegeneration are pathological hallmarks of progressive multiple sclerosis (MS) that underlie cognitive impairments. Neural precursor cells (NPCs) that reside in the hippocampus support cognition through adult neurogenesis. However, with MS chronicity, hippocampal neurogenesis declines that results in memory and learning impairments. Currently, the underlying mechanisms that drive NPC senescence in chronic MS are largely unknown. Here, we have linked downregulation of Neuregulin-1beta 1 (Nrg-1β1) to hippocampal neurodegeneration, neurogenic decline and memory impairment in mice with chronic brain demyelination. Nrg-1β1 is a key factor for neural differentiation that we previously reported its downregulation in chronic human MS lesions. Here, extensive in vivo and in vitro characterizations revealed that therapeutic restoration of Nrg-1β1 can reactivate NPCs and foster hippocampal repair by neurogenesis, synapse reassembly and remyelination that reverses memory impairments. Transcriptomics of NPC progenies confirmed upregulation of genes associated with myelination, synaptic resilience, and cellular homeostasis, underscoring the potential of Nrg-1β1 in activating regenerative mechanisms within the chronically demyelinated hippocampus. Moreover, in comparison with Siponimod, a leading disease modifying therapy for secondary progressive MS, Nrg1β1 treatment achieved multifaceted and greater reparative effects. These new findings introduce Nrg1β1 as a disease relevant candidate with promising therapeutic potential for progressive MS.

ORGANISM(S): Mus musculus

PROVIDER: GSE287967 | GEO | 2026/03/24

REPOSITORIES: GEO

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Project description:Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.

Project description:BACKGROUND: Ochratoxin A (OTA) have made it a serious hazard to food safety worldwide that poses a serious health risk to humans. Our previous research showed that Walnut green husk polysaccharides (WGP) can effectively alleviate intestinal inflammation and intestinal microbiota disturbances caused by OTA. The present study further explored whether WGP can prevents OTA-induced cognitive impairments and elucidate its neuroprotective mechanism. Here, we established fecal microbiota transplantation, Lactobacillus johnsonii (L.john) and Akkermansia muciniphila (AKK) colonization, L.john and AKK-derived extracellular vesicles (EVs), as well as 5-HT and short-chain fatty acid (SCFA) supplementation tests to evaluate the role of the intestinal microbiota and its metabolites in WGP in alleviating OTA-induced cognitive impairment. RESULTS: OTA exposure induced cognitive impairments and inhibition of hippocampal neurogenesis, which was reversed by WGP supplementation. Meanwhile, WGP supplementation significantly reversed OTA-induced gut dysbacteriosis and low abundance of L.john and AKK, high proinflammation factor levels and low neurotransmitter levels in serum, intestine and hippocampus, as well as low SCFA levels in fecal. Antibiotic cocktail treatment eliminates the neuroprotective effect of WGP on OTA-treated mice. In addition, transplantation of the OTA-gut microbiota into normal mice causing similar results to OTA treatment, and these changes were alleviated with the transplantation of OTA+WGP-gut microbiota. Furthermore, colonization with L.john and AKK markedly reversed OTA-induced cognitive impairments and inhibition of hippocampal neurogenesis, as well as increased 5-HT and SCFA levels. EVs derived from L.john and AKK exhibit consistent performance with colonized L.john and AKK, and also have superior abilities in alleviating OTA-induced cognitive impairment and inhibiting hippocampal neurogenesis. Moreover, as a key regulatory factor of microbiota-gut-brain axis, 5-HT and SCFA supplementation significantly alleviated OTA-induced cognitive impairment and inhibition of hippocampal neurogenesis. CONCLUSIONS: Taken together, this work provides new evidence for microbiota-gut-brain axis involved in the neuroprotective effects of WGP on OTA-induced cognitive dysfunction. L.john, AKK and its derived EVs mediate the ameliorative effects of WGP on OTA-induced cognitive impairment. A feasible mechanism is that WGP increased the content of L.john, AKK and its derived EVs, which improve 5-HT and SCFA production in colon to ameliorate cognitive impairment and enhance hippocampal neurogenesis.

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Therapeutic reactivation of hippocampal progenitors reverses cognition decline in progressive brain demyelination

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