Experimental menopause in 3xTg-AD mice exacerbates metabolic, inflammatory, and osteologic phenotypes aligned with Alzheimer's disease pathology.

Background: Alzheimer's disease (AD) is neurodegenerative disease characterized by the accumulation of amyloid-beta plaques and phosphorylated tau. An estimated 7.2 million Americans are currently living with AD, nearly two-thirds of which are women. Sex differences in AD prevalence and pathology are well established, however the mechanisms underlying these differences are understudied. There are compelling links between menopause and AD, but few established common molecular mechanisms partly due to the lack of representative experimental models. Methods and results: Here, we induce an accelerated ovarian failure (OF) model of menopause in the triple-transgenic AD (3xTg-AD) mouse, using ovotoxin 4-vinylcyclohexene diepoxide (VCD) mediated follicular depletion, leading to a loss of circulating progesterone and an increase in plasma follicle-stimulating hormone (FSH) levels-hormonal changes that closely mirror those observed in human menopause. OF exacerbated peripheral phenotypes associated with AD, namely insulin resistance, inflammation, and bone mass and architecture modifications resembling osteoporosis. OF aggravated age-related impaired glucose tolerance and caused insulin resistance. Additionally, plasma levels of four proinflammatory cytokines- IL-5, IL-6, TNF-α, and CXCL- were all increased in OF mice compared to non-menopausal AD mice. Meanwhile, OF mice display heightened bone loss phenotype, a condition with known links to AD risk and pathology. Conclusion: In summary, accelerated ovarian failure presents key metabolic, inflammatory, and skeletal phenotypes associated with AD, indicating that it can be useful for the identification of novel therapeutic targets.