The pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau aggregation in AD remain elusive. The incidence of AD is increased in patients with type 2 diabetes (T2DM), which is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. However, the molecular mechanisms bridging AD and T2DM remain unknown. We first examined the presence of IAPP in the neurofibrillary tangles of AD patients. Then we tested the effect of IAPP on tau aggregation. The biochemical and biological characteristics of the IAPP-tau fibrils were tested in vitro. The seeding activity and neurotoxicity of the IAPP-tau fibrils were confirmed in cultured neurons. Lastly, the effect of IAPP on tau pathology and cognitive impairments was determined by injecting the IAPP-tau fibrils and IAPP fibrils into the hippocampus of tau P301S mice. We found that IAPP interacts with tau and accelerates the formation of a more toxic strain, which shows distinct morphology with enhanced seeding activity and neurotoxicity in vitro. Intrahippocampal injection of the IAPP-tau strain into the tau P301S transgenic mice substantially promoted the spreading of tau pathology and induced more severe synapse loss and cognitive deficits, when compared with tau fibrils. Furthermore, intracerebral injection of synthetic IAPP fibrils initiated tauopathy in the brain of tau P301S transgenic mice. These observations indicate that IAPP acts as a crucial mediator of tau pathology in AD, and provide a mechanistic explanation for the higher risk of AD in individuals with T2DM.

中文翻译：

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胰岛淀粉样多肽交叉种子 tau 并驱动阿尔茨海默病的神经原纤维病理学

tau 蛋白的病理性积累和聚集是包括阿尔茨海默病 (AD) 在内的 tau 蛋白病的标志。然而，介导 AD 中 tau 聚集的分子机制仍然难以捉摸。2型糖尿病（T2DM）患者AD的发病率增加，其特征是胰岛淀粉样多肽（IAPP）在胰腺中的淀粉样沉积。然而，桥接 AD 和 T2DM 的分子机制仍然未知。我们首先检查了 AD 患者神经原纤维缠结中 IAPP 的存在。然后我们测试了 IAPP 对 tau 聚集的影响。在体外测试了 IAPP-tau 原纤维的生化和生物学特性。IAPP-tau 原纤维的播种活性和神经毒性在培养的神经元中得到证实。最后，IAPP 对 tau 病理和认知障碍的影响是通过将 IAPP-tau 原纤维和 IAPP 原纤维注射到 tau P301S 小鼠的海马中来确定的。我们发现 IAPP 与 tau 相互作用并加速形成更具毒性的菌株，该菌株在体外显示出独特的形态，具有增强的播种活性和神经毒性。与 tau 原纤维相比，将 IAPP-tau 菌株海马内注射到 tau P301S 转基因小鼠中显着促进了 tau 病理学的扩散并诱导更严重的突触丧失和认知缺陷。此外，脑内注射合成 IAPP 原纤维在 tau P301S 转基因小鼠的大脑中引发了 tau 病变。这些观察表明 IAPP 是 AD 中 tau 病理学的关键介质，