Wei Zenghui, Koya Jagadish, Reznik Sandra E
Department of Pharmaceutical Sciences, St. John's University, New York, NY, United States.
Department of Pathology, Albert Einstein College of Medicine, New York, NY, United States.
Front Neurosci. 2021 Jul 19;15:687157. doi: 10.3389/fnins.2021.687157. eCollection 2021.
Alzheimer disease (AD) is a chronic neurodegenerative disease that accounts for 60-70% of dementia and is the sixth leading cause of death in the United States. The pathogenesis of this debilitating disorder is still not completely understood. New insights into the pathogenesis of AD are needed in order to develop novel pharmacologic approaches. In recent years, numerous studies have shown that insulin resistance plays a significant role in the development of AD. Over 80% of patients with AD have type II diabetes (T2DM) or abnormal serum glucose, suggesting that the pathogenic mechanisms of insulin resistance and AD likely overlap. Insulin resistance increases neuroinflammation, which promotes both amyloid β-protein deposition and aberrant tau phosphorylation. By increasing production of reactive oxygen species, insulin resistance triggers amyloid β-protein accumulation. Oxidative stress associated with insulin resistance also dysregulates glycogen synthase kinase 3-β (GSK-3β), which leads to increased tau phosphorylation. Both insulin and amyloid β-protein are metabolized by insulin degrading enzyme (IDE). Defects in this enzyme are the basis for a strong association between T2DM and AD. This review highlights multiple pathogenic mechanisms induced by insulin resistance that are implicated in AD. Several pharmacologic approaches to AD associated with insulin resistance are presented.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，占痴呆症病例的60 - 70%，是美国第六大死因。这种使人衰弱的疾病的发病机制仍未完全明确。为了开发新的药物治疗方法，需要对AD的发病机制有新的认识。近年来，大量研究表明胰岛素抵抗在AD的发展中起重要作用。超过80%的AD患者患有2型糖尿病（T2DM）或血糖异常，这表明胰岛素抵抗和AD的致病机制可能重叠。胰岛素抵抗会增加神经炎症，进而促进淀粉样β蛋白沉积和异常的tau蛋白磷酸化。胰岛素抵抗通过增加活性氧的产生，触发淀粉样β蛋白的积累。与胰岛素抵抗相关的氧化应激还会使糖原合酶激酶3-β（GSK-3β）失调，导致tau蛋白磷酸化增加。胰岛素和淀粉样β蛋白都由胰岛素降解酶（IDE）代谢。该酶的缺陷是T2DM与AD之间密切关联的基础。本综述重点介绍了胰岛素抵抗诱导的、与AD相关的多种致病机制。还介绍了几种针对与胰岛素抵抗相关的AD的药物治疗方法。
