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

Background: Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-beta (A beta) 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 A beta 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 A beta 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 orNDfeeding, 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-beta accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induceBACE1post-modifications whichmaycontribute to AD pathogenesis.