Amyloid angiopathy and variability in amyloid β deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease
Amyloid angiopathy and variability in amyloid β deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease
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DOI：
10.1016/s0002-9440(10)64688-3
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发表时间：
2001-06-01
影响因子：
6
通讯作者：
Iwatsubo, T
中科院分区：
文献类型：
--
作者：
Mann, DMA;Pickering-Brown, SM;Iwatsubo, T
早老素（PS）是含有β-连环蛋白的大分子复合物的组成部分，其功能是γ-分泌酶。我们在此报告淀粉样血管病与PS-1连锁的阿尔茨海默病中突变位置之间的显著相关性。在54例早发性家族性阿尔茨海默病病例中，沉积在大脑额叶皮质中的淀粉样β蛋白（AP（42（43）），而不是A β（40））的量增加，其中包括早老素-1（PS）中的25个突变与散发性阿尔茨海默病相比，1）基因。PS-1阿尔茨海默氏病中A β（40）的量根据载脂蛋白E基因ε 4等位基因的拷贝数而变化。虽然A β（40）和A β（42（43））的沉积量与突变的遗传位置没有严格的线性关系，但组织学特征确实存在差异。密码子1 ~ 200位突变者额叶皮质弥漫性斑块多，核心斑块少，轻度或中度淀粉样血管病变;密码子200位后突变者额叶皮质弥漫性斑块多，但核心斑块数量增多，体积增大（即使ε 4等位基因不存在），并且这些通常聚集在受淀粉样血管病严重影响的血管周围。类似地，不同的组织学特征，主要根据淀粉样血管病变的程度，见于小脑。因此，PS-1基因的突变可能改变PS-1蛋白的拓扑结构，从而有利于A β的形成和沉积，但也促进淀粉样血管病，特别是在突变位于密码子200以外的情况下。最后，我们报告说，A β（40）的量，沉积在大脑中与产生的量在文化中的细胞轴承等效突变。
The presenilins (PSs) are components of large molecular complexes that contain beta -catenin and function as gamma -secretase, We report here a striking correlation between amyloid angiopathy and the location of mutation in PS-1 linked Alzheimer's disease. The amount of amyloid beta protein, AP(42(43)), but not A beta (40), deposited in the frontal cortex of the brain is increased in 54 cases of early-onset familial Alzheimer's disease, encompassing 25 mutations in the presenilin-1 (PS-1) gene, compared to sporadic Alzheimer's disease. The amount of A beta (40) in PS-1 Alzheimer's disease varied according to the copy number of epsilon4 alleles of the Apolipoprotein E gene. Although the amounts of A beta (40) and A beta (42(43)) deposited did not correlate with the genetic location of the mutation in a strict linear sense, the histological profile did so vary. Cases with mutations between codon 1 and 200 showed, in frontal cortex, many diffuse plaques, few cored plaques, and mild or moderate amyloid angiopathy, Cases with mutations occurring after codon 200 also showed many diffuse plaques, but the number and size of cored plaques were increased (even when epsilon4 allele was not present) and these were often clustered around blood vessels severely affected by amyloid angiopathy, Similarly, diverging histological profiles, mainly according to the degree of amyloid angiopathy, were seen in the cerebellum. Mutations in the PS-1 gene may therefore alter the topology of the PS-1 protein so as to favor A beta formation and deposition, generally, but also to facilitate amyloid angiopathy particularly in cases in which the mutation lies beyond codon 200. Finally we report that the amount of A beta (40), deposited in the brain correlated with the amount of this produced in culture by cells bearing the equivalent mutations.