McGeer P L, Kawamata T, McGeer E G
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada.
Rev Neurosci. 1998;9(1):1-15. doi: 10.1515/revneuro.1998.9.1.1.
Presenilin-1 (PS-1) is localized to chromosome 14 and presenilin-2 (PS-2) to chromosome 1. Mutations in these genes, primarily in PS-1, account for an estimated 60% of early onset familial Alzheimer's disease cases (FAD), while FAD cases account for about 10% of all Alzheimer's disease (AD) cases. The mutations are minor but are 100% penetrant, suggesting that the proteins have acquired a toxic gain in function. The proteins have multiple transmembrane domains and have been reported to be localized to the Golgi apparatus, endoplasmic reticulum, nuclear membranes and cell surface membranes. They are thought to have functions associated with vesicular trafficking, Notch signaling and apoptosis. PS mutants show relative increases in the amount of A beta42/43 compared with A beta40 in plasma, fibroblasts and brain, observations which have been taken as a possible mechanism of their role in AD. In brain, the mRNAs for these two genes are localized primarily in neurons, with the strongest in situ hybridization signals being observed in the hippocampus, cerebellum and cerebral cortex. In AD, signals detected in the hippocampus are weaker than those in normals, while signals in the cerebellum are comparable. Immunohistochemical localization of the proteins is also primarily in neurons, and, at least for PS-1, is reduced in AD affected areas. PS-1 is localized to granular structures which are most abundant in cell bodies and dendrites. The functions of the presenilins are not yet known, but available evidence points to pyramidal neurons as the most logical site for pathological change in AD.
早老素-1（PS-1）定位于14号染色体，早老素-2（PS-2）定位于1号染色体。这些基因的突变，主要是PS-1的突变，估计占早发型家族性阿尔茨海默病（FAD）病例的60%，而FAD病例约占所有阿尔茨海默病（AD）病例的10%。这些突变虽小但外显率为100%，表明这些蛋白质获得了功能上的毒性增益。这些蛋白质有多个跨膜结构域，据报道定位于高尔基体、内质网、核膜和细胞表面膜。它们被认为具有与囊泡运输、Notch信号传导和细胞凋亡相关的功能。与血浆、成纤维细胞和大脑中的β淀粉样蛋白40相比，PS突变体显示β淀粉样蛋白42/43的量相对增加，这些观察结果被视为它们在AD中发挥作用的一种可能机制。在大脑中，这两个基因的mRNA主要定位于神经元，在海马体、小脑和大脑皮层观察到最强的原位杂交信号。在AD中，海马体中检测到的信号比正常情况下弱，而小脑中的信号相当。这些蛋白质的免疫组织化学定位也主要在神经元中，至少对于PS-1来说，在AD受累区域会减少。PS-1定位于颗粒结构，这些结构在细胞体和树突中最为丰富。早老素的功能尚不清楚，但现有证据表明锥体细胞是AD病理变化最合理的部位。
