Institute of Anatomy and Histology & Embryology, Neuroscience, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, People's Republic of China.
Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, People's Republic of China.
Exp Neurol. 2020 Dec;334:113490. doi: 10.1016/j.expneurol.2020.113490. Epub 2020 Sep 30.
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) have a common pathology. Both diseases are characterized by local deposition of amyloid proteins in the brain or islet organ, but their phenotypes and clinical manifestation vary widely. Although the sources of islet amyloid polypeptide (IAPP) and amyloid beta (Aβ) are independent, their fibrillar sequences are highly homologous. The prevalence of AD in T2DM populations is considerably higher than that in the normal population, but a mechanistic linkage remains elusive. Therefore, the present study aimed to explore the effects of Aβ42 deposition in the brain on the persistently expression of human IAPP (hIAPP). Additionally, cognitive ability, synaptic plasticity, the state of neural stem cells and mitochondrial function were evaluated at 2 or 6 months after stereotaxically injected the oligomer Aβ into the dentate gyrus of hIAPP mice or the wild-type littermates. We found that Aβ and amylin were co-located in hippocampus and Aβ levels increased when Aβ was injected in hIAPP transgenic mice compared with that of the wild-type littermates. Furthermore, at 6 months after Aβ injection in hIAPP mice, it exhibits exacerbated AD-related pathologies including Aβ deposition, cognitive impairment, synapse reduction, neural stem cells exhaustion and mitochondrial dysfunction. Our present study suggested that hIAPP directly implicated the Aβ production and deposition as an important linkage between T2DM and AD.
阿尔茨海默病（AD）和 2 型糖尿病（T2DM）具有共同的病理学。这两种疾病的特征都是大脑或胰岛器官中淀粉样蛋白的局部沉积，但它们的表型和临床表现却大不相同。虽然胰岛淀粉样多肽（IAPP）和淀粉样β（Aβ）的来源是独立的，但它们的纤维序列高度同源。在 T2DM 人群中，AD 的患病率明显高于正常人群，但机制联系仍不清楚。因此，本研究旨在探讨脑内 Aβ42 沉积对人 IAPP（hIAPP）持续表达的影响。此外，在立体定向注射寡聚体 Aβ 到 hIAPP 小鼠或野生型同窝仔鼠的齿状回 2 或 6 个月后，评估认知能力、突触可塑性、神经干细胞状态和线粒体功能。我们发现 Aβ 和淀粉样蛋白在海马中共定位，并且当 Aβ 注射到 hIAPP 转基因小鼠中时，Aβ 水平增加，与野生型同窝仔鼠相比。此外，在 hIAPP 小鼠注射 Aβ 6 个月后，其表现出更严重的 AD 相关病理，包括 Aβ 沉积、认知障碍、突触减少、神经干细胞耗竭和线粒体功能障碍。我们的研究表明，hIAPP 直接参与 Aβ 的产生和沉积，是 T2DM 和 AD 之间的重要联系。
