Dataset Information

LIVER EXERCISE FACTOR REVERSES AGING AND ALZHEIMER’S-RELATED MEMORY LOSS BY TARGETING BRAIN VASCULATURE

ABSTRACT: Blood factors transfer the benefits of exercise to the aged brain. However, mechanisms to restore cognition and the translational application to neurodegenerative disorders are unknown. Here we show that liver-derived exercise factor glycosylphosphatidylinositol (GPI)-specific phospholipase D1(Gpld1)–a GPI-degrading enzyme–reverses aging and Alzheimer’s-related memory loss by targeting brain vasculature. Increasing Gpld1 rejuvenated transcriptional hippocampal aging signatures at a single cell level and rescued memory in aged mice. Mechanistically, we identified GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on brain vasculature as a GPLD1 substrate. Mimicking an age-related increase in cerebrovascular TNAP impaired memory in young mice and mitigated Gpld1-mediated cognitive benefits in aged mice. Inhibiting TNAP activity recapitulated the benefits of Gpld1 in old age. In an Alzheimer’s disease model, increasing Gpld1, or inhibiting TNAP, ameliorated A pathology and improved cognitive deficits. Collectively, our data identify cerebrovasculature as a gatekeeper of the restorative cognitive benefits of a liver-to-brain exercise axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE269061 | GEO | 2026/03/11

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:We utilized an unbiased RNA-sequencing approach to uncover genes in the dorsal hippocampus that are differentially expressed under conditions where exercise benefits are maintained throughout sedentary delay periods and enable the formation of long-term memory and synaptic plasticity. Engagement in different exercise parameters resulted in a diverse transcriptional profile as defined by differences in the number, pattern, and type of genes up and down-regulated. To identify genes that play a critical role in cognitive enhancement, we next focused our attention on exercise groups that enable robust long-term memory formation under inadequate subthreshold acquisition sessions of the hippocampus-dependent object location memory task. By intersecting up regulated genes when exercise facilitated learning, we identify potential regulators of learning and targets for memory enhancement. We identify a gene coding for a type 1 membrane receptor and kinase for the TGF-β family of signaling molecules, Acvr1c as one of few genes showing upregulation in conditions where exercise enabled the formation of long-term memory, indicating a gate-type role for Acvr1c in memory consolidation. In addition to overall gene expression levels, we identify potential regulators upstream of gene targets within the window for cognitive enhancement. Additionally, we use three complementary analyses to examine the mechanisms responsible for maintaining the ‘molecular memory window’ for exercise utilizing up regulated differentially expressed genes compared to sedentary controls. These analyses include: gene coexpression network analysis to identify potential hub genes for each exercise condition, predicted pathways altered by exercise, and gene ontology enrichment analysis of cellular components altered by exercise. Together, results identify Acvr1c as one of few genes up regulated only under conditions where exercise enabled the formation of long-term memory and synaptic plasticity, suggesting a role for Acvr1c in facilitation of memory consolidation. Follow up experiments manipulating ACVR1C function, find that it serves as an essential bidirectional regulator of long-term memory formation capable of alleviating impairments in hippocampus-dependent memory and synaptic plasticity associated with age and Alzheimer’s Disease.

Dataset Information

LIVER EXERCISE FACTOR REVERSES AGING AND ALZHEIMER’S-RELATED MEMORY LOSS BY TARGETING BRAIN VASCULATURE

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets