高脂饮食引起的胰岛素抵抗促进小鼠的脑淀粉样病变
  • 分别利用长期高脂饮食喂养(HFD)和胰岛素受体底物(IRS-2)基因敲除,构建2种不同的胰岛素抵抗+阿尔兹海默症(AD)小鼠模型,监测大脑淀粉样蛋白(Aβ)和体内胰岛素动力学;
  • HFD糖尿病AD模型小鼠对外周胰岛素刺激的脑反应降低,脑与血浆的胰岛素比值降低,细胞间隙Aβ清除减少,脑淀粉样病变恶化;
  • 饮食干预可逆地缓解上述症状,HFD也能够加速ISR-2缺陷AD小鼠的脑Aβ沉积;
  • Aβ沉积及淀粉样病变与饮食导致的胰岛素抵抗相关且可逆。
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《Molecular Neurodegeneration》上发表的一项最新研究,发现在不同阿尔兹海默症小鼠模型中,高脂饮食可通过引起小鼠大脑中的胰岛素抵抗,以促进淀粉样蛋白的沉积及淀粉样病变,饮食干预可缓解上述症状,提示饮食引起的胰岛素抵抗或与大脑中的淀粉样病变有因果关联。
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Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease

饮食和基因诱导的脑胰岛素抵抗对阿尔茨海默病小鼠模型淀粉样蛋白病理的差异性影响

10.1186/s13024-019-0315-7

2019-04-12, Article

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BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

First Authors:
Tomoko Wakabayashi

Correspondence Authors:
Takeshi Iwatsubo

All Authors:
Tomoko Wakabayashi,Kazuki Yamaguchi,Kentaro Matsui,Toshiharu Sano,Tetsuya Kubota,Tadafumi Hashimoto,Ayako Mano,Kaoru Yamada,Yuko Matsuo,Naoto Kubota,Takashi Kadowaki,Takeshi Iwatsubo

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