Itzhaki Ruth F, Wozniak Matthew A
Faculty of Life Sciences, The University of Manchester, Moffat Building, PO Box 88, Sackville Street, Manchester M60 1QD, UK.
Prog Lipid Res. 2006 Jan;45(1):73-90. doi: 10.1016/j.plipres.2005.11.003. Epub 2005 Dec 15.
Almost a hundred years ago, the main neuropathological features of Alzheimer's disease (AD) brain were discovered, yet the underlying cause(s) are still unknown, and the disease is basically untreatable. Despite the very numerous studies on the neuropathological features, the cause(s) of their production and whether they have an aetiological role in the disease or are merely end-products ("tombstones") are still unknown. Indeed, until fairly recently, the only known risk factors were age, Down's syndrome and head injury. A susceptibility factor, the type 4 allele of the apolipoprotein E gene was identified, but it is neither essential nor sufficient to cause AD, so other factors must be involved also. We investigated the possibility of a viral role and discovered that HSV1 DNA is present in brain of a high proportion of elderly people and that in combination with APOE-epsilon4 it confers a high risk of AD. Subsequently, we found that APOE determines outcome of infection in several diseases caused by diverse infectious agents. Here we describe our studies, and the few others carried out elsewhere, on the mechanism of action of HSV1 and the dependence of the damage on APOE. We discuss, in relation to HSV1 action on lipids and to the spread of the virus via lipid rafts in brain, the possible involvement in AD of cholesterol, a vital and major component of the human brain, and the dispute over whether statins, drugs used for lowering cholesterol levels, are protective against the disease. We also link the damage due to two major consequences of HSV1 infection--inflammatory and oxidative processes--to lipid peroxidation in brain, and consider the influence of the different apoE isoforms in this process.
大约一百年前，阿尔茨海默病（AD）大脑的主要神经病理学特征就已被发现，但潜在病因仍然未知，且该疾病基本无法治愈。尽管对神经病理学特征进行了大量研究，但其产生的原因以及它们在疾病中是具有病因学作用还是仅仅是终产物（“墓碑”）仍然未知。事实上，直到最近，已知的唯一风险因素是年龄、唐氏综合征和头部损伤。一种易感性因素，即载脂蛋白E基因的4型等位基因已被确定，但它既不是导致AD的必要条件也不是充分条件，所以必然还涉及其他因素。我们研究了病毒发挥作用的可能性，发现相当一部分老年人的大脑中存在单纯疱疹病毒1型（HSV1）DNA，并且它与APOE-ε4相结合会带来患AD的高风险。随后，我们发现APOE决定了由多种感染因子引起的几种疾病的感染结果。在此，我们描述我们的研究以及其他地方进行的少数相关研究，内容涉及HSV1的作用机制以及损伤对APOE的依赖性。我们结合HSV1对脂质的作用以及病毒在大脑中通过脂筏传播的情况，讨论了胆固醇（人类大脑的一种重要且主要的成分）可能与AD有关，以及关于用于降低胆固醇水平的药物他汀类药物是否对该疾病具有保护作用的争议。我们还将HSV1感染的两个主要后果——炎症和氧化过程——所导致的损伤与大脑中的脂质过氧化联系起来，并考虑了不同载脂蛋白E异构体在这个过程中的影响。
