Cai Zhiyou, Xiao Ming, Chang Liying, Yan Liang-Jun
Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan Renmin Hospital, No. 39 Chaoyang Middle Road, Shiyan, 442000, Hubei Province, People's Republic of China,
Metab Brain Dis. 2015 Aug;30(4):839-51. doi: 10.1007/s11011-014-9631-3. Epub 2014 Nov 16.
A critical role of insulin resistance (IR) in Alzheimer's disease (AD) includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles (NFTs), failure of synaptic transmission and neuronal degeneration. Aβ is sequentially cleavaged from APP by two proteolytic enzymes: β-secretase and γ-secretase. IR could regulate Aβ production via enhancing β- and γ-secretase activity. Meanwhile, IR induces oxidative stress and inflammation in the brain which contributes to Aβ and tau pathology. Aβ accumulation can enhance IR through Aβ-mediated inflammation and oxidative stress. IR is a possible linking between amyloid plaques and NFTs pathology via oxidative stress and neuroinflammation. Additionally, IR could disrupt acetylcholine activity, and accelerate axon degeneration and failures in axonal transport, and lead to cognitive impairment in AD. Preclinical and clinical studies have supported that insulin could be useful in the treatment of AD. Thus, an effective measure to inhibit IR may be a novel drug target in AD.
胰岛素抵抗（IR）在阿尔茨海默病（AD）中的关键作用包括β-淀粉样蛋白（Aβ）的产生和积累、神经原纤维缠结（NFTs）的形成、突触传递失败和神经元变性。Aβ通过两种蛋白水解酶：β-分泌酶和γ-分泌酶依次从淀粉样前体蛋白（APP）上裂解下来。IR可通过增强β-和γ-分泌酶活性来调节Aβ的产生。同时，IR诱导大脑中的氧化应激和炎症，这有助于Aβ和tau病理变化。Aβ积累可通过Aβ介导的炎症和氧化应激增强IR。IR可能通过氧化应激和神经炎症在淀粉样斑块和NFTs病理之间建立联系。此外，IR可破坏乙酰胆碱活性，加速轴突变性和轴突运输失败，并导致AD患者认知障碍。临床前和临床研究均支持胰岛素可能对AD治疗有用。因此，抑制IR的有效措施可能是AD的一种新型药物靶点。
