| First Author | Lv S | Year | 2023 |
| Journal | Aging Cell | Volume | 22 |
| Issue | 9 | Pages | e13932 |
| PubMed ID | 37594184 | Mgi Jnum | J:340448 |
| Mgi Id | MGI:7526852 | Doi | 10.1111/acel.13932 |
| Citation | Lv S, et al. (2023) ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl-CoA level. Aging Cell 22(9):e13932 |
| abstractText | Although aging and apolipoprotein E (APOE) epsilon4 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. |
