Estrogen deprivation exacerbates Alzheimer’s disease pathology through neuronal CTSS signaling [scRNA-Seq]

Single-nucleus RNA sequencing revealed widespread transcriptional reprogramming across brain cell types following estrogen deprivation, with prominent upregulation of the lysosomal protease cathepsin S (Ctss) and the AD risk gene ApoE. Remarkably, partial genetic reduction of CTSS completely reversed OVX-induced Aβ accumulation, glial activation, and cognitive impairment in female 5xFAD mice, establishing CTSS as a critical downstream mediator of estrogen deficiency-driven pathology.

Our findings provide mechanistic insights into sex-biased AD vulnerability and identify cathepsin S as a promising therapeutic target for mitigating AD risk in postmenopausal women.Our findings provide mechanistic insight into sex-biased AD vulnerability and identify cathepsin S as a promising therapeutic target for mitigating AD risk in postmenopausal women.