J Neuroendocrinol. 2026 Mar;38(3):e70161. doi: 10.1111/jne.70161.
ABSTRACT
More women than men are diagnosed with Alzheimer's disease (AD). Sex hormones have been ascribed neuroprotective properties, and their decline, particularly the reduction of estrogen during menopause, has been implicated in AD risk. In this study, we examined how loss of circulating sex hormones affects cognitive performance and amyloid pathology in two mouse models of AD, the aggressive AppNL-G-F and the slower AppNL-F models of brain amyloidosis. Bilateral gonadectomy was induced in both male and female AppNL-G-F and AppNL-F mice. Pathology was assessed using cognitive tests and histological evaluations of amyloid depositions and neuroinflammation. Serum and brain estrogen and testosterone levels were measured by ELISA, and the expression of key estrogenic signaling genes was evaluated using qPCR. We report that female gonadectomy had little impact on behavior or pathology in the AppNL-G-F model, whereas male gonadectomy improved learning and reduced hippocampal amyloid depositions. In the AppNL-F model, gonadectomy worsened amyloid pathology in both sexes. Hormone analysis revealed that significant levels of estrogen in females, but not testosterone in males, remain partly preserved in the brain after gonadectomy, and that low testosterone levels associate with increased insulin-like growth factor 1 (IGF-1) expression which may play a compensatory role in maintaining estrogenic signaling. Our study provides new insights into how the loss of circulating sex hormones influences brain sex hormone levels and AD pathology and contributes to a better understanding of the sex differences observed in this disease.
PMID:41808585 | PMC:PMC12976827 | DOI:10.1111/jne.70161