Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Innovation Center for Medical Redox Navigation, Incubation Center for Advanced Medical Science, Kyushu University, Fukuoka, Japan.
Sci Rep. 2018 Feb 16;8(1):3213. doi: 10.1038/s41598-018-21426-6.
Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (-/-) mice. p66Shc (-/-) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (-/-) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.
越来越多的证据表明，糖尿病与痴呆症，尤其是阿尔茨海默病（AD）有关。然而，其潜在机制尚不清楚。一些研究表明氧化应激（OS）是糖尿病并发症发病机制中的主要因素之一。在这里，我们展示了 OS 参与糖尿病动物模型的脑损伤，除了淀粉样蛋白-β的积累外，该模型至少部分通过与 AD 病理无关的机制介导。我们使用 p66Shc 基因敲除（-/-）小鼠研究了 p66Shc 信号通路对与糖尿病相关的认知衰退的贡献。p66Shc（-/-）小鼠的大脑中氧化应激较少，并且对糖尿病引起的脑损伤具有抗性。此外，p66Shc（-/-）糖尿病小鼠表现出明显较少的认知功能障碍，以及氧化应激水平降低和小胶质细胞数量减少。这项研究提出了 p66Shc 介导的炎症级联反应导致 OS 作为与糖尿病相关的认知障碍的致病机制，至少部分通过与 AD 病理无关的机制介导。
