The impacts of menopause on a mouse model of co‐morbid metabolic syndrome and Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is the leading cause of disability and 5th cause of death in people over 65 years of age. Approximately 2/3 of AD patients are women, most of whom are postmenopausal. Menopause is linked with cognitive changes in women: younger age at menopause is associated with worse cognitive outcomes. Moreover, menopause accelerates mid-life risk factors for dementia, by increasing risk for cardiovascular and cerebrovascular disease and metabolic disease which is by itself a risk factor for dementia. We have previously shown that female 3xTg-AD mice are more greatly impacted cognitively and metabolically by a high fat diet when compared to males. We therefore hypothesized that menopause would exacerbate both metabolic and cognitive impairment and pathology in a mouse model of AD. Female App NL-F mice were placed on either low fat (LF; 10% fat) or high fat (HF; 60% fat; metabolic disease model) diet for 7 months. An accelerated ovarian failure model of menopause (4-vinylcyclohexene diepoxide) was used at diet onset and female estrus cycles were monitored to determine menopause onset. Metabolic status was assessed by tracking weight gain and assessing glucose tolerance. Mice were then subjected to a battery of behavioral tests before being euthanized and brains and serum were collected. Menopausal mice tended to be more metabolically impaired (worse glucose tolerance) regardless of diet. Cognitive impairment differences between groups were investigated using several behavioral tests. Neither menopause nor HF diet affected anxiety-like behavior (open field testing), however HF diet decreased general activity levels. Novel object recognition testing demonstrated that menopause, regardless of diet, impaired episodic-like memory. Additionally, HF diet, regardless of menopause, impaired spatial learning (assessed via Barnes maze testing). We are currently evaluating the underlying pathology in the brain that could mediate these cognitive deficits (i.e. Amyloid pathology, white matter damage and neuroinflammation). We hope that this work will highlight the need to model endocrine aging in animal models of dementia and will contribute to further understanding of the interaction between metabolic disease and menopause in the scope of AD.