Li Hsin-Hua, Lin Chih-Li, Huang Chien-Ning
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, China.
Institute of Medicine, Chung Shan Medical University; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, China.
Neural Regen Res. 2018 Feb;13(2):198-206. doi: 10.4103/1673-5374.226379.
A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer's disease (AD). In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β (Aβ) levels by affecting amyloid precursor protein (APP) cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuroprotective effects against AD. Statins may play a beneficial role in reducing Aβ-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing Aβ-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase (AMPK) in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.
越来越多的证据表明，脂质代谢稳态的破坏会影响阿尔茨海默病（AD）的发病机制。特别是，据报道大脑中胆固醇稳态的失调会显著增加患AD的风险。因此，脂质稳态的失调可能通过影响淀粉样前体蛋白（APP）的切割来增加β淀粉样蛋白（Aβ）水平，而APP切割是AD发病机制中最重要的风险因素。先前的研究表明，Aβ可引发神经元胰岛素抵抗，这在AD中对Aβ诱导的神经毒性的反应中起重要作用。流行病学研究还表明，使用他汀类药物与AD发病率降低有关。因此，他汀类药物被认为是对AD具有神经保护作用的良好候选药物。他汀类药物可能在降低Aβ诱导的神经毒性方面发挥有益作用。它们的作用涉及一种推测的机制，该机制超出了其在预防Aβ诱导的神经毒性方面的降胆固醇作用。然而，他汀类药物保护作用的潜在分子机制在Aβ诱导的神经毒性中尚未明确确定。鉴于他汀类药物可能提供超出抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的益处，这些药物也可能改善大脑。因此，他汀类药物可能通过激活神经元细胞中的AMP活化蛋白激酶（AMPK）对受损的胰岛素信号产生有益影响。它们在靶向Aβ介导的神经毒性方面发挥潜在的治疗作用。
