Based on epidemiological and experimental studies, type 2 diabetes mellitus (T2DM), especially insulin resistance that comprises the core mechanism of T2DM, has been recognized as a significant risk factor for Alzheimer’s disease (AD). Studies in humans and diabetic AD model mice have indicated a correlation between insulin resistance and increased amyloid deposition in the brain. Paradoxically, mice with targeted disruption of genes involved in the insulin signaling pathway showed protective effects against the AD-related pathology. These conflicting observations raise an issue as to the relationship between dysregulation of insulin signaling and AD pathophysiology. To study the causal relations and molecular mechanisms underlying insulin resistance-induced exacerbation of amyloid pathology, we investigated the chronological changes in the development of insulin resistance and amyloid pathology in two independent insulin-resistant AD mouse models, i.e., long-term high-fat diet (HFD) feeding and genetic disruption of Irs2, in combination with dietary interventions. In addition to biochemical and histopathological analyses, we examined the in vivo dynamics of brain amyloid-β (Aβ) and insulin by microdialysis technique. HFD-fed diabetic AD model mice displayed a reduced brain response to peripheral insulin stimulation and a decreased brain to plasma ratio of insulin during the hyperinsulinemic clamp. Diet-induced defective insulin action in the brain was accompanied by a decreased clearance of the extracellular Aβ in vivo and an exacerbation of brain amyloid pathology. These noxious effects of the HFD both on insulin sensitivity and on Aβ deposition in brains were reversibly attenuated by dietary interventions. Importantly, HFD feeding accelerated Aβ deposition also in the brains of IRS-2-deficient AD mice. Our results suggested a causal and reversible association of brain Aβ metabolism and amyloid pathology by diet-dependent, but not genetically-induced, insulin-resistance. These observations raise the possibility that the causal factors of insulin resistance, e.g., metabolic stress or inflammation induced by HFD feeding, but not impaired insulin signaling per se, might be directly involved in the acceleration of amyloid pathology in the brain.

中文翻译：

---

饮食和遗传诱导的脑胰岛素抵抗对阿尔茨海默氏病小鼠模型淀粉样蛋白病理学的差异作用

根据流行病学和实验研究，已认识到2型糖尿病（T2DM），尤其是构成T2DM核心机制的胰岛素抵抗，是阿尔茨海默病（AD）的重要危险因素。对人类和糖尿病AD模型小鼠的研究表明，胰岛素抵抗与大脑中淀粉样蛋白沉积增加之间存在相关性。矛盾的是，靶向破坏胰岛素信号通路基因的小鼠表现出针对AD相关病理的保护作用。这些矛盾的观察提出了胰岛素信号失调与AD病理生理之间关系的问题。要研究胰岛素抵抗引起的淀粉样蛋白病情恶化的因果关系和分子机制，我们在两个独立的胰岛素抵抗性AD小鼠模型（即长期高脂饮食（HFD）喂养和Irs2的基因破坏）中结合饮食干预研究了胰岛素抵抗和淀粉样蛋白病理学发展的时间变化。除了生化和组织病理学分析，我们还通过微透析技术检查了脑淀粉样蛋白β（Aβ）和胰岛素的体内动力学。由HFD喂养的糖尿病AD模型小鼠在高胰岛素钳制过程中表现出对周围胰岛素刺激的脑反应降低，以及胰岛素的脑与血浆比率降低。饮食引起的脑部胰岛素作用缺陷伴随着体内细胞外Aβ清除率的降低和脑淀粉样蛋白病理学的恶化。通过饮食干预，HFD对胰岛素敏感性和对大脑中Aβ沉积物的这些有害作用均被可逆地减弱。重要的是，在IRS-2缺陷型AD小鼠的大脑中，HFD喂养也加速了Aβ的沉积。我们的研究结果表明，饮食依赖性的但不是遗传诱导的胰岛素抵抗是大脑Aβ代谢与淀粉样蛋白病理之间的因果关系和可逆关系。这些发现增加了胰岛素抵抗的病因，例如由HFD喂养引起的代谢应激或炎症，但本身并未损害胰岛素信号传导，可能直接参与了大脑淀粉样蛋白病理的加速。HFD喂养也加速了IRS-2缺陷型AD小鼠的大脑中Aβ的沉积。我们的研究结果表明，饮食依赖性的但不是遗传诱导的胰岛素抵抗是大脑Aβ代谢与淀粉样蛋白病理之间的因果关系和可逆关系。这些发现增加了胰岛素抵抗的病因，例如由HFD喂养引起的代谢应激或炎症，但本身并未损害胰岛素信号传导，可能直接参与了大脑淀粉样蛋白病理的加速。HFD喂养也加速了IRS-2缺陷型AD小鼠的大脑中Aβ的沉积。我们的研究结果表明，饮食依赖性的但不是遗传诱导的胰岛素抵抗是大脑Aβ代谢与淀粉样蛋白病理之间的因果关系和可逆关系。这些发现增加了胰岛素抵抗的病因，例如由HFD喂养引起的代谢应激或炎症，但本身并未损害胰岛素信号传导，可能直接参与脑内淀粉样蛋白病理的加速。