Interaction Between a High-Fat Diet and Tau Pathology in Mice: Implications for Alzheimer’s Disease

Article type: Research Article

Authors: Jang, Yu Jung^{a; b; 1} | Choi, Min Gyu^{a; 1} | Yoo, Byung Jae^a | Lee, Kyeong Jae^{a; b} | Jung, Won Beom^c | Kim, Seong-Gi^{c; d} | Park, Sun Ah^{a; b; e; *}

Affiliations: [a] Lab for Neurodegenerative Dementia, Department of Anatomy, Ajou University School of Medicine, Suwon, Republic of Korea | [b] Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea | [c] Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon, Republic of Korea | [d] Department of Biomedical Engineering, Sungkyunkwan University, Suwon, Republic of Korea | [e] Department of Neurology, Ajou University School of Medicine, Suwon, Republic of Korea

Correspondence: [*] Correspondence to: Sun Ah Park, Lab for Neurodegenerative Dementia, Department of Anatomy and Department of Neurology, Ajou University School of Medicine; Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea. Tel.: +82 31 219 5030; Fax: +82 31 219 5039; E-mail: sap001@ajou.ac.kr.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Obesity is a modifiable risk factor for Alzheimer’s disease (AD). However, its relation with tau pathology (i.e., aberrant tau protein behavior in tauopathies such as AD) has been inconclusive. Objective:This study investigated the interaction between a high-fat diet (HFD) and tau pathology in adult male mice. Methods:Transgenic mice overexpressing human P301S Tau (those with the pathology) and wild-type (WT) littermates were subjected to behavioral tests, functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and western blotting analysis to investigate the effects of prolonged HFD versus regular diet during adulthood. Results:HFD increased body weight in both WT and P301S mice but had minimal effect on blood glucose levels. The brain response to HFD was tau genotype-specific. WT mice exhibited decreased recognition memory and enhanced network connectivity in fMRI, while P301S mice exhibited white matter tract disorganization in DTI as the sole significant finding. The reduction of insulin receptor β, insulin downstream signaling, neuronal nuclear protein, CD68-positive phagocytic activity, and myelin basic protein level were confined to the cortex of WT mice. In contrast to P301S mice, WT mice showed significant changes in the tau protein and its phosphorylation levels along with increased soluble neurofilament light levels in the hippocampus. Conclusions:HFD-induced brain dysfunction and pathological changes were blunted in mice with the pathology and more profound in healthy mice. Our findings highlight the need to consider this interaction between obesity and tau pathology when tailoring treatment strategies for AD and other tauopathies.

Keywords: Alzheimer’s disease, diffusion tensor image, functional magnetic resonance image, high-fat diet, obesity, tau, transgenic mice, white matter integrity

DOI: 10.3233/JAD-230927

Journal: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 485-506, 2024