Presenilin transgenic mice as models of Alzheimer's disease.
Presenilin transgenic mice as models of Alzheimer's disease.
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DOI：
10.1007/s00429-009-0227-3
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发表时间：
2010-03
影响因子：
3.1
通讯作者：
Hof, Patrick R.
中科院分区：
文献类型：
--
作者：
Elder, Gregory A.;Sosa, Miguel A. Gama;De Gasperi, Rita;Dickstein, Dara L.;Hof, Patrick R.
关键词：
早老素-1（PS1）和早老素-2（PS2）的突变导致家族性阿尔茨海默病（FAD）。早老素影响多个分子途径，并且最为人所知的是它们在γ-分泌酶切割I型跨膜蛋白（包括淀粉样前体蛋白（APP））中的作用。已经使用多种启动子产生了PS1和PS2 FAD突变转基因小鼠。PS1相关的FAD突变也被敲入内源性小鼠基因。PS FAD突变小鼠始终显示Aβ42升高，对Aβ40几乎无影响。当与形成噬斑的APP FAD突变体系杂交时，PS1 FAD突变体引起更早和更广泛的噬斑沉积。虽然单转基因PS1或PS2小鼠不形成斑块，但它们表现出许多病理特征，包括年龄相关的神经元和突触损失以及血管病理。它们还表现出对兴奋性毒性损伤的敏感性增加，最有可能是基于从内质网过度释放钙。在年轻的PS1 FAD突变小鼠中，海马的电生理长时程增强增加，但这种效应似乎随着年龄的增长而消失。在大多数研究中，成年海马的神经发生也受到PS1 FAD突变体的损害。在成年前脑中PS1在PS2无效背景（PS1/2 cDKO）上被条件性敲除的小鼠发展出惊人的神经变性，其模拟AD神经病理学，与神经元和突触损失、星形胶质细胞增生和tau过度磷酸化相关，尽管其不伴随斑块沉积。PS转基因小鼠作为AD模型的相关性进行了讨论。
Mutations in presenilin-1 (PS1) and presenilin-2 (PS2) cause familial Alzheimer’s disease (FAD). Presenilins influence multiple molecular pathways and are best known for their role in the γ-secretase cleavage of type I transmembrane proteins including the amyloid precursor protein (APP). PS1 and PS2 FAD mutant transgenic mice have been generated using a variety of promoters. PS1-associated FAD mutations have also been knocked into the endogenous mouse gene. PS FAD mutant mice consistently show elevations of Aβ42 with little if any effect on Aβ40. When crossed with plaque forming APP FAD mutant lines, the PS1 FAD mutants cause earlier and more extensive plaque deposition. Although single transgenic PS1 or PS2 mice do not form plaques, they exhibit a number of pathological features including age-related neuronal and synaptic loss as well as vascular pathology. They also exhibit increased susceptibility to excitotoxic injury most likely on the basis of exaggerated calcium release from the endoplasmic reticulum. Electrophysiologically long-term potentiation in the hippocampus is increased in young PS1 FAD mutant mice but this effect appears to be lost with aging. In most studies neurogenesis in the adult hippocampus is also impaired by PS1 FAD mutants. Mice in which PS1 has been conditionally knocked out in adult forebrain on a PS2 null background (PS1/2 cDKO) develop a striking neurodegeneration that mimics AD neuropathology in being associated with neuronal and synaptic loss, astrogliosis and hyperphosphorylation of tau, although it is not accompanied by plaque deposits. The relevance of PS transgenic mice as models of AD is discussed.
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