Wijesekara Nadeeja, Ahrens Rosemary, Sabale Miheer, Wu Ling, Ha Kathy, Verdile Giuseppe, Fraser Paul E
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada;
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
FASEB J. 2017 Dec;31(12):5409-5418. doi: 10.1096/fj.201700431R. Epub 2017 Aug 14.
Alzheimer's disease (AD) and type 2 diabetes (T2D) present a significant risk to each other. AD and T2D are characterized by deposition of cerebral amyloid-β (Aβ) and pancreatic human islet amyloid polypeptide (hIAPP), respectively. We investigated the role of amyloidogenic proteins in the interplay between these diseases. A novel double transgenic mouse model combining T2D and AD was generated and characterized. AD-related amyloid transgenic mice coexpressing hIAPP displayed peripheral insulin resistance, hyperglycemia, and glucose intolerance. Aβ and IAPP amyloid co-deposition increased tau phosphorylation, and a reduction in pancreatic β-cell mass was detected in islets. Increased brain Aβ deposition and tau phosphorylation and reduced insulin levels and signaling were accompanied by extensive synaptic loss and decreased neuronal counts. Aβ immunization rescued the peripheral insulin resistance and hyperglycemia, suggesting a role for Aβ in T2D pathogenesis for individuals predisposed to AD. These findings demonstrate that Aβ and IAPP are key factors in the overlapping pathologies of AD and T2D.-Wijesekara, N., Ahrens, R., Sabale, M., Wu, L., Ha, K., Verdile, G., Fraser, P. E. Amyloid-β and islet amyloid pathologies link Alzheimer's disease and type 2 diabetes in a transgenic model.
阿尔茨海默病（AD）和2型糖尿病（T2D）相互之间存在重大风险。AD和T2D分别以脑淀粉样β蛋白（Aβ）沉积和胰腺人胰岛淀粉样多肽（hIAPP）沉积为特征。我们研究了淀粉样蛋白在这些疾病相互作用中的作用。构建并表征了一种结合T2D和AD的新型双转基因小鼠模型。共表达hIAPP的AD相关淀粉样转基因小鼠表现出外周胰岛素抵抗、高血糖和葡萄糖不耐受。Aβ和IAPP淀粉样蛋白共沉积增加了tau蛋白磷酸化，并且在胰岛中检测到胰腺β细胞数量减少。脑Aβ沉积增加、tau蛋白磷酸化增加以及胰岛素水平和信号转导降低伴随着广泛的突触丧失和神经元数量减少。Aβ免疫可挽救外周胰岛素抵抗和高血糖，这表明Aβ在易患AD的个体的T2D发病机制中起作用。这些发现表明，Aβ和IAPP是AD和T2D重叠病理中的关键因素。-维杰塞卡拉，N.，阿伦斯，R.，萨巴尔，M.，吴，L.，哈，K.，韦尔迪勒，G.，弗雷泽，P.E. 淀粉样β蛋白和胰岛淀粉样病理在转基因模型中将阿尔茨海默病和2型糖尿病联系起来。
