The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology
The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology
复制标题
DOI：
10.1038/nm1096-1146
复制
发表时间：
1996-10-01
期刊：
影响因子：
82.9
通讯作者：
Arango, JCV
中科院分区：
文献类型：
--
作者：
Lemere, CA;Lopera, F;Arango, JCV
早老素1 （PS1）基因的错义突变导致显性早发性家族性阿尔茨海默病（FAD）的最常见形式（1,2），并与基因携带者血浆和皮肤成纤维细胞培养基中以残基42 （A β 42）结尾的淀粉样β肽（A β）水平升高有关(3)。β 42很容易聚集，似乎为随后的β 40聚集提供了一个中心（参考文献4），导致无数神经斑块的形成。为了获得PS1突变如何在如此早的年龄引起AD病理的体内信息，我们对来自哥伦比亚一个大型亲属的4名PS1- fad患者的神经病理表型进行了表征(5)，这些患者携带密码子280 Glu To Ala取代（Glu280Ala） PS1突变(2)。利用A β替代羧基末端的特异性抗体，我们检测到A β 42在许多脑区大量沉积，这是AD患者最早和主要的斑块A β形式（参考文献6-8）。计算机辅助量化显示，与12例散发性AD患者相比，4例PS1-FAD患者大脑中a β 42负荷显著增加，但a β 40负荷无显著增加。严重的小脑病理包括大量的A β 42反应性斑块，许多营养不良的神经突和反应性胶质细胞。我们在脑组织中的结果与最近PS1- fad患者中A β 42水平升高的生化证据一致，并强烈表明突变的PS1蛋白改变了A β的c端β淀粉样前体蛋白的蛋白水解过程，有利于A β 42的沉积。
Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD)(1,2) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers(3). A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred(5) bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation(2). Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42 but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A beta to favor deposition of A beta 42.