Faculty Proceedings, Presentations, Speeches and Lectures

Title

Females Have It Worse: In Mouse Models of Alzheimer's Disease and Mixed Dementia Females Are More Severely Affected By A High Fat Diet Than Males

Event Title

Neuroscience 2021 50th Annual Meeting: Interdisciplinary, Innovative, Inclusive

Event Location

Virtual

Document Type

Poster

Presentation Date

11-11-2021

Date Range

2021-11-08 to 2021-11-11

Description

Diabetes and prediabetes are major risk factors for all-cause dementia. 1 in 10 people in the United States currently have diabetes- a figure that is on the rise. Prediabetes is even more common, affecting roughly 1 in 3 in the U.S. who are frequently unaware of this diagnosis. There is much to learn about how prediabetes can contribute to dementia decades later and examining this relationship may unveil new targets or emphasize prediabetes as a risk factor. Here we examine the impact of prediabetes on two of the most common types of dementia: Alzheimer’s disease (AD) and mixed dementia (MxD) which is the overlap between AD and vascular pathology. Furthermore, given that there are sex differences in both the prevalence and presentation of dementia types, we ask if prediabetes influences males and females differently. There is evidence to suggest the heightened severity of diabetes as a dementia risk factor for women: women with diabetes have a 19% greater risk of vascular dementia than men with diabetes. We hypothesize that female mice will face a greater degree of pathology in response to prediabetes modeled by a high fat diet and that this will exacerbate AD and vascular pathology in mouse models of AD and MxD. Using male and female B6129SF2/J mice as wild type (WT) controls, we modeled AD using the 3xTg-AD mouse model of Alzheimer’s disease and MxD by performing a unilateral common carotid artery occlusion surgery to produce chronic cerebral hypoperfusion. To model prediabetes, we administered a high fat diet (60% fat). Control mice received a control diet (10% fat). We found that high fat diet led to greater metabolic effects in females (increased weight gain and glucose intolerance) and that this was exacerbated by 3xTg-AD genotype in females only. We measured classical features of AD pathology: astrogliosis and beta-amyloid burden using IHC and tau pathology using western blot. We have found that females had greater levels of hippocampal astrogliosis and cortical beta-amyloid positive cells than males with no effect of diet. However, MxD trended toward increasing amyloid pathology only in high fat fed females (p=0.06). In sum, our findings demonstrate increased sensitivity of females to the negative metabolic effects of high fat diet and the pathological effects of AD and MxD.

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