Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Alzheimers Res Ther. 2013 May 21;5(3):24. doi: 10.1186/alzrt178. eCollection 2013.
Genetic studies have provided the best evidence for cause and effect relationships in Alzheimer's disease (AD). Indeed, the identification of deterministic mutations in the APP, PSEN1 and PSEN2 genes and subsequent preclinical studies linking these mutations to alterations in Aβ production and aggregation have provided pivotal support for the amyloid cascade hypothesis. In addition, genetic, pathologic and biological studies of APOE have also indicated that the genetic risk for AD associated with APOE4 can be attributed, at least in part, to its pro-amyloidogenic effect on Aβ. In recent years a number of SNPs that show unequivocal genome-wide association with AD risk have implicated novel genetic loci as modifiers of AD risk. However, the functional implications of these genetic associations are largely unknown. For almost all of these associations, the functional variants have not been identified. Very recently, two large consortiums demonstrated that rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene confer significant risk for AD. TREM2 is a type 1 membrane receptor protein primarily expressed on microglia in the central nervous system that has been shown to regulate phagocytosis and activation of monocytes. Previously it had been shown that homozygous loss of function mutations in TREM2 cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, Nasu Hakola disease) and also a pure form of early-onset dementia. The association of TREM2 variants with AD brings innate immune signaling into the light, affirming innate immunity's role as a significant factor in AD pathogenesis.
遗传研究为阿尔茨海默病（AD）的因果关系提供了最佳证据。事实上，APP、PSEN1 和 PSEN2 基因中确定突变的鉴定以及随后将这些突变与 Aβ产生和聚集的改变联系起来的临床前研究为淀粉样蛋白级联假说提供了重要支持。此外，APOE 的遗传、病理和生物学研究也表明，与 APOE4 相关的 AD 遗传风险至少部分归因于其对 Aβ的促淀粉样蛋白形成作用。近年来，一些显示与 AD 风险明确全基因组关联的 SNPs 表明，新的遗传位点是 AD 风险的修饰因子。然而，这些遗传关联的功能意义在很大程度上尚不清楚。对于几乎所有这些关联，功能变体尚未确定。就在最近，两个大型联盟表明，髓样细胞表达的触发受体 2（TREM2）基因中的罕见变异赋予 AD 显著风险。TREM2 是一种 1 型膜受体蛋白，主要在中枢神经系统的小胶质细胞上表达，已被证明可调节单核细胞的吞噬作用和激活。先前已经表明，TREM2 纯合功能丧失突变会导致多囊脂膜性骨发育不良伴硬化性白质脑病（PLOSL，Nasu Hakola 病）以及纯早发性痴呆。TREM2 变体与 AD 的关联将先天免疫信号带入了人们的视野，肯定了先天免疫在 AD 发病机制中的重要作用。
