Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding.
Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding.
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DOI：
10.1038/mp.2016.230
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发表时间：
2017-09
影响因子：
11
通讯作者：
Soto C
中科院分区：
文献类型：
--
作者：
Moreno-Gonzalez I;Edwards Iii G;Salvadores N;Shahnawaz M;Diaz-Espinoza R;Soto C
大量流行病学研究表明，2 型糖尿病 (T2D) 患者患阿尔茨海默病 (AD) 的风险显着较高，但目前尚不清楚造成这种关联的分子机制。这两种疾病都被认为是与蛋白质聚集体积累相关的蛋白质错误折叠疾病。 AD 期间大脑中的 β 淀粉样蛋白 (Aβ) 和 tau 蛋白，以及 T2D 期间胰岛中的胰岛淀粉样蛋白多肽 (IAPP)。这些蛋白质的形成和积累遵循种子成核模型，其中错误折叠的聚集体或“种子”促进天然蛋白质的快速错误折叠和聚集。我们的基本假设是，T2D 中产生的错误折叠 IAPP 通过交叉接种 Aβ 来增强 AD 病理学，从而为这些疾病之间的联系提供了分子解释。在这里，我们研究了错误折叠的 IAPP 如何在体外和体内影响 Aβ 聚集和 AD 病理。我们观察到，添加 IAPP 种子会以类似种子的方式在体外加速 Aβ 聚集，并且产生的原纤维由两种肽组成。与 AD 转基因小鼠或患有 1 型糖尿病 (T1D) 的 AD 转基因动物相比，表达两种人类蛋白的转基因动物表现出加剧的 AD 样病理。值得注意的是，IAPP 与脑实质沉积物中的淀粉样斑块共定位，表明这些肽可能直接相互作用并加重疾病。此外，将胰腺 IAPP 聚集体接种到 AD 转基因小鼠的大脑中会导致比未经治疗的动物更严重的 AD 病理学和显着更大的记忆障碍。该数据为一种新的疾病机制提供了概念验证，该机制涉及错误折叠蛋白质通过交叉播种事件的相互作用，这可能有助于加速或加剧疾病发病机制。我们的研究结果有助于理解 T2D 和 AD（两种最常见的蛋白质错误折叠疾病）之间的联系。
Numerous epidemiological studies have shown a significantly higher risk for development of Alzheimer’s disease (AD) in patients affected by type 2 diabetes (T2D), but the molecular mechanism responsible for this association is presently unknown. Both diseases are considered protein misfolding disorders associated to the accumulation of protein aggregates; amyloid-beta (Aβ) and tau in the brain during AD, and islet amyloid polypeptide (IAPP) in pancreatic islets in T2D. Formation and accumulation of these proteins follows a seeding-nucleation model, where a misfolded aggregate or “seed” promotes the rapid misfolding and aggregation of the native protein. Our underlying hypothesis is that misfolded IAPP produced in T2D potentiates AD pathology by cross-seeding Aβ, providing a molecular explanation for the link between these diseases. Here, we examined how misfolded IAPP affects Aβ aggregation and AD pathology in vitro and in vivo. We observed that addition of IAPP seeds accelerates Aβ aggregation in vitro in a seeding-like manner and the resulting fibrils are composed of both peptides. Transgenic animals expressing both human proteins exhibited exacerbated AD-like pathology compared to AD transgenic mice or AD transgenic animals with type-1 diabetes (T1D). Remarkably, IAPP colocalized with amyloid plaques in brain parenchymal deposits, suggesting these peptides may directly interact and aggravate the disease. Furthermore, inoculation of pancreatic IAPP aggregates into the brains of AD transgenic mice resulted in more severe AD pathology and significantly greater memory impairments than untreated animals. This data provides a proof-of-concept for a new disease mechanism involving the interaction of misfolded proteins through cross-seeding events which may contribute to accelerate or exacerbate disease pathogenesis. Our findings could shed light on understanding the linkage between T2D and AD, two of the most prevalent protein misfolding disorders.