Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes
Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes
复制标题
DOI：
10.1073/pnas.1000645107
复制
发表时间：
2010-04-13
影响因子：
11.1
通讯作者：
Morishita, Ryuichi
中科院分区：
文献类型：
--
作者：
Takeda, Shuko;Sato, Naoyuki;Morishita, Ryuichi
最近的流行病学研究表明，糖尿病是阿尔茨海默病的强烈危险因素。然而，潜在的机制在很大程度上仍不清楚。在这项研究中，为了研究这些疾病之间的病理生理相互作用，我们建立了反映这两种疾病的病理条件的动物模型。我们将阿尔茨海默病转基因小鼠(APP23)与两种类型的糖尿病小鼠(肥胖/肥胖和NSY小鼠)杂交，并对它们的代谢和脑病理进行了分析。在双突变(app(+)-ob/ob)小鼠中，糖尿病的发作加剧了阿尔茨海默样认知功能障碍，而没有增加脑淀粉样β蛋白负荷。值得注意的是，APP(+)-ob/ob小鼠表现出脑血管炎症和严重的淀粉样血管病变。相反，与ob/ob小鼠相比，杂交小鼠表现出加速的糖尿病表型，这表明阿尔茨海默病淀粉样蛋白病理可能会加重糖尿病。同样，APP(+)-NSY融合小鼠比糖尿病NSY小鼠表现出更严重的糖耐量异常。此外，高脂饮食喂养诱导了APP(+)-NSY小鼠严重的记忆障碍，而没有增加脑淀粉样β蛋白负荷。在这里，我们建立了早发认知功能障碍的阿尔茨海默病小鼠模型。脑血管改变和脑内胰岛素信号的改变可能在这一关系中起着关键作用。这些发现可能会为这种激烈辩论的联系提供洞察力。
Recent epidemiological studies suggest that diabetes mellitus is a strong risk factor for Alzheimer disease. However, the underlying mechanisms remain largely unknown. In this study, to investigate the pathophysiological interaction between these diseases, we generated animal models that reflect the pathologic conditions of both diseases. We crossed Alzheimer transgenic mice (APP23) with two types of diabetic mice (ob/ob and NSY mice), and analyzed their metabolic and brain pathology. The onset of diabetes exacerbated Alzheimer-like cognitive dysfunction without an increase in brain amyloid-beta burden in double-mutant (APP(+)-ob/ob) mice. Notably, APP(+)-ob/ob mice showed cerebrovascular inflammation and severe amyloid angiopathy. Conversely, the cross-bred mice showed an accelerated diabetic phenotype compared with ob/ob mice, suggesting that Alzheimer amyloid pathology could aggravate diabetes. Similarly, APP(+)-NSY fusion mice showed more severe glucose intolerance compared with diabetic NSY mice. Furthermore, high-fat diet feeding induced severe memory deficits in APP(+)-NSY mice without an increase in brain amyloid-beta load. Here, we created Alzheimer mouse models with early onset of cognitive dysfunction. Cerebrovascular changes and alteration in brain insulin signaling might play a pivotal role in this relationship. These findings could provide insights into this intensely debated association.