High Fat Diet Aggravates AD-Related Pathogenic Processes in APP/PS1 Mice

Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder and negative lifestyle factors may contribute to its etiopathogenesis. Substantial evidence from humans and murine models reveals that Insulin Resistance (IR) associated with a high fat diet (HFD) increases the risk of developing AD and age-related amyloidogenesis. Objective: The aim of the study was to corroborate and clarify the influence of HFD on amyloidogenesis and cognitive deficits in AD model mice. Methods: We here show that a four months HFD-feeding increases IR in both the periphery and brain of APP/PS1 mice, which are used as AD models. Meanwhile, long-term HFD exacerbates cognitive defects and impairs dendritic integrity and expressions of synaptic proteins in APP/PS1 mice. Furthermore, HFD induces an increase in f3-secretase (BACE1) expression and a decrease in insulin-degrading enzyme (IDE) expression, resulting in f3-amyloid (Af3) accumulation. Conclusion: Our data suggest that long-term HFD, with the accompanying IR, promotes Af3 toxicity and cognitive deficits, indicating that modifiable lifestyle hazards such as HFD-induced IR might contribute to AD pathogenesis.