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 β-secretase (BACE1) expression and a decrease in
insulin-degrading enzyme (IDE) expression, resulting in β-amyloid (Aβ) accumulation.
Conclusion: Our data suggest that long-term HFD, with the accompanying IR, promotes Aβ toxicity
and cognitive deficits, indicating that modifiable lifestyle hazards such as HFD-induced IR
might contribute to AD pathogenesis.