Posted by The association between cellular senescence and ABCA1 expression in human postmortem brain samples was studied using transcriptomic, histological, and biochemical analyses. Unbiased proteomic screening was performed to identify the proteins that mediate cellular ABCA1 trafficking. The authors created ABCA1 knock out cell lines and mouse models to validate the role of ABCA1 in cholesterol-induced mTORC1 activation and senescence. They used APOE4-TR mice and induced pluripotent stem cell (iPSC) models to explore cholesterol-ABCA1-senescence pathways.
Treatment of APOE4-TR mice with HPBCD reduced brain oxysterol levels, ABCA1 lysosome trapping, mTORC1 activation, and attenuated senescence and neuroinflammation markers. Human induced pluripotent stem cell (hiPSC)-derived astrocytes with APOE4/4 genotype were cultured. When these human iPSc-derived astrocytes were treated with methyl-β-cyclodextrin (MeβCD) after LDL loading, cellular cholesterol accumulation and IL-1β and CCL2 mRNA levels were decreased.
Oxysterol accumulation in APOE4 and AD induced ABCA1 and caveolin-1 expression, contributing to lysosomal dysfunction and increased cellular senescence markers. Reduction of oxysterol by HPCD reduces mTORC1 activation, senescence and neuroinflammation in APOE4-TR mice.
This study provides novel insights into how cholesterol metabolism accelerates features of brain cellular senescence pathway and identifies therapeutic targets to mitigate these processes.
Wang, S., Li, B., Li, J. et al. Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD. Mol Neurodegeneration 20, 15 (2025). https://doi.org/10.1186/s13024-025-00802-7