Effects of menopause on cognitive deficits in a mouse model of metabolic disease.

Abstract

By 2025, it is estimated that nearly 20% of the U.S. population will be post-menopausal women. Menopause accelerates metabolic disease, a major mid-life risk factor for dementia. Indeed, ∼80% of those with dementia have concurrent metabolic disease and nearly all women with dementia are post-menopausal. We hypothesize that menopause will exacerbate the metabolic and cognitive effects of a high fat diet. Using young-adult and middle-aged C57BL/6J female mice (N= 9-15/group), we modeled metabolic disease via chronic administration of high fat (HF; 60%) diet vs. low fat (LF; 10% fat) control diet. We modeled menopause via daily injections of 4-vinylcyclohexene diepoxide (VCD), which results in accelerated ovarian failure vs. vehicle. To confirm menopause, we performed daily vaginal cytology. We performed a glucose tolerance test (GTT) at 2.5 months and 7 months on the diet. We assessed deficits in spatial memory (object place recognition test) and episodic-like memory (novel object recognition test). There was a main effect of menopause in increasing glucose intolerance, and % weight gain. Longer time in menopause was associated with greater visceral fat accumulation in HF-fed mice. Spatial memory and episodic-like memory were impaired by age, high fat diet, and menopause. The spatial memory deficits were worse in middle-aged menopausal mice compared to the young menopausal mice. Our data show that post-menopausal mice have greater metabolic impairment than pre-menopausal mice, regardless of age. However, deficits in spatial memory due to HF diet or menopause increase with age. This is in line with clinical data showing that post-menopausal women are more susceptible to metabolic disease and are at increased risk for cognitive impairment and dementia. Altogether, our data highlight the importance of considering endocrine age distinctly from chronological age in studies of dementia.