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.

背景：阿尔茨海默病 (AD) 是最常见的神经退行性疾病，消极的生活方式因素可能导致其发病。来自人类和小鼠模型的大量证据表明，与高脂肪饮食 (HFD) 相关的胰岛素抵抗 (IR) 会增加患 AD 和与年龄相关的淀粉样蛋白生成的风险。

目的：本研究的目的是证实和阐明 HFD 对 AD 模型小鼠淀粉样变性和认知缺陷的影响。

方法：我们在此表明​​，四个月的 HFD 喂养会增加 APP/PS1 小鼠（用作 AD 模型）的外周和大脑的 IR。同时，长期HFD会加剧APP/PS1小鼠的认知缺陷并损害树突完整性和突触蛋白的表达。此外，HFD 诱导 β-分泌酶 (BACE1) 表达增加和胰岛素降解酶 (IDE) 表达减少，导致 β-淀粉样蛋白 (Aβ) 积累。

结论：我们的数据表明，长期 HFD 伴随着 IR，促进 Aβ 毒性和认知缺陷，表明可改变的生活方式危害，如 HFD 诱导的 IR，可能有助于 AD 发病机制。