Posted by Cellular senescence, a hallmark of aging, has been implicated in Alzheimer’s disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However, the role of ABCA1 trafficking in cellular senescence associated with APOE4 and AD remains unclear.
In this study it was demonstrated that oxysterol accumulation in APOE4 and AD promotes greater expression of ABCA1 and caveolin-1, which endocytoses and traps ABCA1 in lysosomes and induces a dysfunctional lysosomal state in which ABCA1 fails to recycle back to the plasma membrane. This process activates the mTORC1 pathway and induces cellular senescence and neuroinflammation. The reduction in oxysterols by methyl beta-cyclodextrin in in vitro experiments decreased lysosomal ABCA1, accelerated endolysosomal recycling, increased the efflux of cholesterol to HDL, and reduced mTORC1 activation, senescence, and neuroinflammation. HPBCD treatment in animal experiments (mice; 2g/kg body weight for 8 weeks) resulted in total cholesterol levels in the brain or plasma not different between HPBCD and PBS groups. However, levels of oxysterols (7-hydroxycholesterol, 25-hydroxycholesterol, and 7α,25-dihydroxycholesterol) were reduced in HPBCD-treated mice compared to controls. Treatment with HPBCD was associated with more efficient cholesterol efflux. HPBCD-treated mice showed improved performance in the novel object recognition test.
The results suggest that restoring cholesterol homeostasis presents a viable therapeutic strategy to mitigate the effects of AD. Unfortunately, to date, no clinical intervention focusing on modulating cholesterol metabolism has been successful in patients with AD. The findings of this study indicate that interventions that induce ABCA1 without accounting for endolysosomal dysfunction may inadvertently accelerate ABCA1 lysosomal sequestration. This concept highlights the importance of drugs or therapeutics that target endolysosomal functions and ABCA1 recycling.
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