Chen Xuesong, Hui Liang, Geiger Jonathan D
Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
Austin J Pharmacol Ther. 2014 Aug 26;2(6).
Altered cholesterol homeostasis in general and increased levels of low-density lipoprotein (LDL) cholesterol specifically is a robust risk factor for the pathogenesis of sporadic Alzheimer's disease (AD). Because of this, the family of drugs known as statins have been tried extensively to lower cholesterol levels in attempting to prevent and/or lessen the neuropathogenesis of AD. Unfortunately, evidence accumulated to date is insufficient to support the continued use of statins as a viable pharmacotherapeutic approach against AD. To understand these complex and inter-related issues it is important to review how altered cholesterol homeostasis contributes to AD pathogenesis and why statins have not provided clinical benefit against AD. Apolipoproteins with their different affinities for various lipids and the receptors that control cholesterol uptake can result in drastic differences in cholesterol trafficking into and its distribution within neurons. The presence of the apoE4 or elevated plasma levels of LDL cholesterol can lead to a set of conditions that resembles lysosomal lipid storage disorders observed in Niemann-Pick type C disease such as impaired recycling of cholesterol back to the endoplasmic reticulum (ER), Golgi and plasma membranes, cholesterol deficiencies in plasma membranes, and increased cholesterol accumulation in endolysosomes resulting in endolysosome dysfunction. Consequently, the use of statins to block cholesterol synthesis in ER might not only decrease further plasma membrane cholesterol levels thus disturbing synaptic integrity, but also could also increase cholesterol burden in endolysosomes thus worsening endolysosome dysfunction. Therefore, it is not surprising that the use of cholesterol-lowering strategies with statins has not resulted in clinical benefit for patients living with AD.
一般而言，胆固醇稳态改变，特别是低密度脂蛋白（LDL）胆固醇水平升高，是散发性阿尔茨海默病（AD）发病机制的一个强大危险因素。因此，人们广泛尝试使用他汀类药物家族来降低胆固醇水平，以预防和/或减轻AD的神经发病机制。不幸的是，迄今为止积累的证据不足以支持继续使用他汀类药物作为对抗AD的可行药物治疗方法。为了理解这些复杂且相互关联的问题，重要的是回顾胆固醇稳态改变如何导致AD发病机制，以及为什么他汀类药物没有为AD提供临床益处。载脂蛋白对各种脂质具有不同的亲和力，以及控制胆固醇摄取的受体，可导致胆固醇进入神经元及其在神经元内分布的巨大差异。载脂蛋白E4的存在或血浆LDL胆固醇水平升高可导致一系列类似于尼曼-匹克C型病中观察到的溶酶体脂质储存障碍的情况，如胆固醇回收到内质网（ER）、高尔基体和质膜的再循环受损、质膜中的胆固醇缺乏以及内溶酶体中胆固醇积累增加导致内溶酶体功能障碍。因此，使用他汀类药物阻断ER中的胆固醇合成不仅可能进一步降低质膜胆固醇水平从而扰乱突触完整性，而且还可能增加内溶酶体中的胆固醇负担，从而使内溶酶体功能障碍恶化。因此，使用他汀类药物降低胆固醇的策略未给AD患者带来临床益处也就不足为奇了。
