Affiliation:
1. Department of Neurology Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University Fuzhou China
2. School of Basic Medical Sciences Fujian Medical University Fuzhou China
3. Department of Pathology the First Affiliated Hospital of Fujian Medical University Fuzhou China
Abstract
AbstractAlthough aging and apolipoprotein E (APOE) ε4 allele have been documented as two major risk factors for late‐onset Alzheimer's disease (LOAD), their interaction and potential underlying mechanisms remain unelucidated. Using humanized ApoE4‐ and ApoE3‐ target replacement mice, we found the accumulation of senescent neurons and the activation of mTOR and endosome‐lysosome‐autophagy (ELA) system in the hippocampus of aged ApoE4 mice. Further analyses revealed that ApoE4 aggravated the profile change of hippocampal transcription and metabolism in an age‐dependent manner, accompanying with an disruption of metabolism, which is presented with the downregulating activity of citrate synthase, the level of ATP and, most importantly, the level of acetyl coenzyme A (Ac‐CoA); GTA supplement, an Ac‐CoA substrate, reversed the senescent characteristics, decreased the activation of mTOR and ELA system, and enhanced the synaptic structure and increasing level of pre‐/post‐synaptic plasticity‐related protein, leading to cognitive improvement in aged ApoE4 mice. These data suggest that ApoE4 exacerbates neuronal senescence due to a deficiency of acetyl‐CoA, which can be ameliorated by GTA supplement. The findings provide novel insights into the potential therapeutic value of GTA supplement for the cognitive improvement in aged APOE4 carriers.
Funder
National Natural Science Foundation of China
Cited by
2 articles.
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