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

TL;DR

Inducing menopause in mice with Alzheimer's disease traits worsens metabolic, inflammatory, and bone-related issues linked to the disease.

Contribution

A novel experimental model linking menopause and Alzheimer's disease pathology through accelerated ovarian failure in 3xTg-AD mice.

Findings

Ovarian failure in mice worsens insulin resistance and glucose tolerance.

Ovarian failure increases proinflammatory cytokines IL-5, IL-6, TNF-α, and CXCL.

Ovarian failure leads to heightened bone loss resembling osteoporosis.

Abstract

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.

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.

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.

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