摘要
阿尔茨海默病(AD)是一种与衰老有关的多因素疾病,在被认为是一个集中介导的过程中,代谢因素导致了阿尔茨海默病的发生。虽然其确切的基本机制尚不明确,但肥胖被认为是导致阿尔茨海默病的关键因素,抗胰岛素性可能使两种病理之间建立联系。我们用高脂饮食的肥胖小鼠(HFD)来探究这两种疾病的分子机制。在APP加工代谢和Aβ积累过程中,高脂饮食喂养的小鼠大脑表现出高水平的APP、 Aβ40/Aβ42、 BACE、GSK3β、GSK3β和tau蛋白。免疫荧光硫磺素T染色实验证明了Aβ生成增加以及不溶物的沉积和斑块在高脂饮食的小鼠海马体和大脑皮层中的形成。不溶性组分中Aβ40/Aβ42的存在通过ELISA实验证实。降低胰岛素受体(IRS)的减少和胰岛素信号转导缺陷证明了大脑胰岛素抗性。研究发现,在促凋亡基因被激活的神经元核中,Akt的磷酸化水平降低,FoxO3a水平有所增加。与胰岛素抗性相关的不同基因失调,特别是那些参与炎症反应和细胞因子合成的基因失调由Profiler PCR 实验进行分析。此外,高脂饮食诱导的氧化应激,线粒体功能障碍和动力学由涉及该过程的生物标志物的表达证明。证据表明,除了胰岛素抗性,肥胖和AD标记都与炎症、脂联素的稳态失衡、氧化应激和线粒体功能障碍有关,所有的这些机制导致了神经退行性疾病。
关键词: 脂肪因子,阿尔茨海默氏病,基因表达,炎症,抗胰岛素性,线粒体功能障碍,肥胖。
Current Alzheimer Research
Title:Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease
Volume: 12 Issue: 8
Author(s): Domenico Nuzzo, Pasquale Picone, Sara Baldassano, Luca Caruana, Elisa Messina, Antonella Marino Gammazza, Francesco Cappello, Flavia Mulè and Marta Di Carlo
Affiliation:
关键词: 脂肪因子,阿尔茨海默氏病,基因表达,炎症,抗胰岛素性,线粒体功能障碍,肥胖。
摘要: Alzheimer’s disease (AD) is an aging-related multi-factorial disorder to which metabolic factors contribute at what has canonically been considered a centrally mediated process. Although the exact underlying mechanisms are still unknown, obesity is recognized as a risk factor for AD and the condition of insulin resistance seems to be the link between the two pathologies. Using mice with high fat diet (HFD) obesity we dissected the molecular mechanisms shared by the two disorders. Brains of HFD fed mice showed elevated levels of APP and Aβ40/Aβ42 together with BACE, GSK3β and Tau proteins involved in APP processing and Aβ accumulation. Immunofluorescence, Thioflavin T staining experiments, confirmed increased Aβ generation, deposition in insoluble fraction and plaques formation in both the hippocampus and the cerebral cortex of HFD mice. Presence of Aβ40/Aβ42 in the insoluble fraction was also shown by ELISA assay. Brain insulin resistance was demonstrated by reduced presence of insulin receptor (IRs) and defects in Akt-Foxo3a insulin signaling. We found reduced levels of phospho-Akt and increased levels of Foxo3a in the nuclei of neurons where proapototic genes were activated. Dysregulation of different genes related to insulin resistance, especially those involved in inflammation and adipocytokines synthesis were analyzed by Profiler PCR array. Further, HFD induced oxidative stress, mitochondrial dysfunction and dynamics as demonstrated by expression of biomarkers involved in these processes. Here, we provide evidence that obesity and AD markers besides insulin resistance are associated with inflammation, adipokine dyshomeostasis, oxidative stress and mitochondrial dysfunction, all mechanisms leading to neurodegeneration.
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Nuzzo Domenico, Picone Pasquale, Baldassano Sara, Caruana Luca, Messina Elisa, Gammazza Marino Antonella, Cappello Francesco, Mulè Flavia and Di Carlo Marta, Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease, Current Alzheimer Research 2015; 12 (8) . https://dx.doi.org/10.2174/1567205012666150710115506
DOI https://dx.doi.org/10.2174/1567205012666150710115506 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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