Effects of Menopause and High Fat Diet on Metabolic Outcomes in a Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Abi-Ghanem, Charly^a | Salinero, Abigail E.^a | Smith, Rachel M.^a | Kelly, Richard D.^a | Belanger, Kasey M.^a | Richard, Riane N.^a | Paul, Aaron S.^a | Herzog, Ava A.^a | Thrasher, Christina A.^a | Rybka, Krystyna A.^b | Riccio, David^a | Gannon, Olivia J.^a | Kordit, David^a | Kyaw, Nyi-Rein^a | Mansour, Febronia M.^a | Groom, Emily^a | Brooks, Heddwen L.^c | Robison, Lisa S.^d | Pumiglia, Kevin^e | Zuloaga, Damian G.^b | Zuloaga, Kristen L.^{a; *}

Affiliations: [a] Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA | [b] Department of Psychology and Center for Neuroscience Research, State University of New York at Albany, Albany, NY, USA | [c] Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA | [d] Department of Psychology and Neuroscience, Nova Southeastern University, Fort Lauderdale, FL, USA | [e] Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, USA

Correspondence: [*] Correspondence to: Kristen L. Zuloaga, PhD, Associate Professor, Department of Neuroscience & Experimental Therapeutics, Albany Medical College, 47 New Scotland Avenue; MC-136, Albany, NY 12208, USA. E-mail: [email protected].

Abstract: Background:About two-thirds of those with Alzheimer’s disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. Objective:Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause. Methods:First, 3-month-old AppNL-F and WT female mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure. Results:Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance. Conclusions:This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD.

Keywords: Alzheimer’s disease, glucose metabolism, hypothalamus, menopause, metabolic disease, obesity

DOI: 10.3233/JAD-231332

Journal: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1177-1194, 2024