High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice

Article type: Research Article

Authors: Bao, Jian^{a; b; *; 1} | Liang, Zheng^{a; 1} | Gong, Xiaokang^a | Yu, Jing^{a; b} | Xiao, Yifan^{a; b} | Liu, Wei^{a; b} | Wang, Xiaochuan^{a; c} | Wang, Jian-Zhi^{a; c} | Shu, Xiji^{a; b; *}

Affiliations: [a] Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China | [b] Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China | [c] Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Correspondence: [*] Correspondence to: Xiji Shu, Institutes of Biomedical Sciences, Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, China. Tel.: +86 18971625295; E-mail: xijishu@jhun.edu.cn; Jian Bao, Institutes of Biomedical Sciences, Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, China. Tel.: +86 13871011874; E-mail: baoj@jhun.edu.cn.

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

Abstract: Background:Alzheimer’s disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated. Objective:The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology. Methods:2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses. Results:A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques. Conclusion:Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

Keywords: Alzheimer’s disease, BACE1, high fat, phosphorylation, SUMOylation

DOI: 10.3233/JAD-215299

Journal: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 863-876, 2022