ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl‐CoA level

Abstract

Although 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.

Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD

“…Cholesterol and lipid accumulation has been reported in cellular and mouse models of Aβ [63, 64], tau [65, 66] and APOE4 [39,[67][68][69]. A recent study identi ed more senescent neurons in the hippocampus of old ApoE4-TR mice than in ApoE3-TR mice owing to dysregulation of ATP and acetyl coenzyme A [14], which are substrates for cholesterol synthesis [70]. Cholesterol localization shifts to lysosomes, leading to the formation of microdomains enriched for the mTORC1 scaffolding complex, priming mTORC1 for activation, and increasing proin ammatory SASP [5,71].…”

“…Apolipoprotein E4 allele (APOE4) is the strongest genetic risk factor for late-onset AD [12,13]. More senescent neurons were found in APOE4-target replacement (APOE4-TR) mice than in APOE3-TR mice [14]. Arguably, APOE4's major effects in the brain are mediated by its cholesterol-transporting capability [15][16][17].…”

Microglial apolipoprotein E particles contribute to neuronal senescence and synaptotoxicity

“…In the current study, we observed neurotoxicity associated with APOE4 -TR microglia compared to APOE3 -TR microglia, which aligns with a recent publication that demonstrates the exacerbation of neuronal senescence in APOE4 -TR mice. 82 This phenotype may be attributed, at least in part, to the larger size of microglial APOE4 particles, because previous studies have linked larger-sized apoE particles with neurotoxicity. 36 , 83 Additionally, we observed lower GPNMB/APOE ratio in APOE4 particles, compared to that in APOE3 particles, suggesting that GPNMB might not be the primary culprit for the neurotoxic effects of microglial APOE4 (data not shown).…”

Cellular senescence in brain aging and cognitive decline

“…Separate from microglia, ApoE4 was recently found to decrease acetyl-CoA levels in hippocampal neurons of elderly ApoE4 mice, resulting in cellular senescence (Lv et al, 2023). Supplying glycerol triacetate (GTA) to increase acetyl-CoA levels to ApoE4 elderly mice decreased cellular senescence in neurons and increased expression of proteins related to synaptic plasticity.…”