Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
Centre for Neuroscience Studies and Department of Psychiatry, Queen's University, Kingston, Canada.
J Pathol. 2021 Jul;254(3):244-253. doi: 10.1002/path.5674. Epub 2021 Apr 29.
Amyloid plaques and neurofibrillary tangles composed of hyperphosphorylated tau are important contributors to Alzheimer's disease (AD). Tau also impacts pancreatic beta cell function and glucose homeostasis. Amyloid deposits composed of islet amyloid polypeptide (IAPP) are a pathological feature of type 2 diabetes (T2D). The current study investigates the role of human tau (hTau) in combination with human IAPP (hIAPP) as a potential mechanism connecting AD and T2D. Transgenic mice expressing hTau and hIAPP in the absence of murine tau were generated to determine the impact of these pathological factors on glucose metabolism. Co-expression of hIAPP and hTau resulted in mice with increased hyperglycaemia, insulin resistance, and glucose intolerance. The hTau-hIAPP mice also exhibited reduced beta cell area, increased amyloid deposition, impaired insulin processing, and reduced insulin content in islets. Tau phosphorylation also increased after stimulation with high glucose. In addition, brain insulin content and signalling were reduced, and tau phosphorylation was increased in these animals. These data support a link between tau and IAPP amyloid, which seems to act co-ordinately to impair beta cell function and glucose homeostasis, and suggest that the combined pathological actions of these proteins may be a potential mechanism connecting AD and T2D. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
淀粉样斑块和神经原纤维缠结由过度磷酸化的 tau 组成，是阿尔茨海默病（AD）的重要致病因素。Tau 还会影响胰腺β细胞功能和葡萄糖稳态。胰岛淀粉样多肽（IAPP）组成的淀粉样沉积物是 2 型糖尿病（T2D）的一种病理特征。本研究探讨了人源 Tau（hTau）与人类 IAPP（hIAPP）结合作为连接 AD 和 T2D 的潜在机制的作用。生成了在缺乏鼠源 Tau 的情况下表达 hTau 和 hIAPP 的转基因小鼠，以确定这些病理因素对葡萄糖代谢的影响。hIAPP 和 hTau 的共表达导致小鼠出现高血糖、胰岛素抵抗和葡萄糖耐量降低。hTau-hIAPP 小鼠的胰岛面积减小，淀粉样沉积物增加，胰岛素处理受损，胰岛素含量减少。在高葡萄糖刺激后，tau 磷酸化也增加。此外，这些动物的大脑胰岛素含量和信号减少，tau 磷酸化增加。这些数据支持 tau 和 IAPP 淀粉样蛋白之间存在联系，这似乎协同作用，损害β细胞功能和葡萄糖稳态，并表明这些蛋白质的联合病理作用可能是连接 AD 和 T2D 的潜在机制。
