Estradiol ameliorates AD pathology and cognitive deficits by SORLA-mediated APP endosomal trafficking.

Alzheimer’s disease (AD) shows a notable female bias in both prevalence and severity. This bias is closely linked to declining estradiol levels during menopause. Our study demonstrated that estradiol can inhibit the accelerated progression of AD caused by ovariectomy (OVX) in female APP/PS1 mice. Transcriptome analysis revealed that estradiol prevented the decline in sortilin-related receptor 1 (Sorl1), which encodes the sorting receptor SORLA, in the hippocampus of female APP/PS1-OVX mice. Neuronal Sorl1 knockdown blocked estradiol’s ability to alleviate AD symptoms. Mechanistically, estradiol enhanced SORLA-mediated redirection of amyloid precursor protein (APP) trafficking from early endosomes toward the Golgi apparatus and lysosomes, which were involved in non-amyloidogenic processing and reducing Aβ levels. Additionally, estradiol promoted estrogen receptor α (ERα) binding to the Sorl1 promoter, thereby activating SORLA expression. Notably, estradiol ameliorated AD progression in female APP/PS1-OVX mice through ERα, and this effect depended on SORLA. Overall, estradiol mitigated AD pathology by activating Sorl1 transcription via ERα, which in turn directed APP endosomal trafficking through SORLA. This pathway provides valuable mechanistic insights into sex differences in AD and highlights potential therapeutic targets.