A mutation in APP protects against Alzheimer's disease and age-related cognitive decline
A mutation in APP protects against Alzheimer's disease and age-related cognitive decline
复制标题
DOI：
10.1038/nature11283
复制
发表时间：
2012-08-02
期刊：
影响因子：
64.8
通讯作者：
Stefansson, Kari
中科院分区：
文献类型：
--
作者：
Jonsson, Thorlakur;Atwal, Jasvinder K.;Stefansson, Kari
据估计，在西方世界60岁以上人群中，痴呆症的患病率超过5%，其中约三分之二是由阿尔茨海默病导致的（1 - 4）。65岁以后，阿尔茨海默病的年龄特异性患病率每5年几乎翻倍，导致90岁以上人群的患病率超过25%（参考文献3）。在此，为了寻找对阿尔茨海默病风险有显著影响的β - 淀粉样前体蛋白（APP）基因的低频变异，我们在一组来自1795名冰岛人的全基因组序列数据中研究了APP的编码变异。我们在APP基因中发现了一种编码突变（A673T），它能预防阿尔茨海默病以及无阿尔茨海默病的老年人的认知能力下降。这种替换发生在APP的天冬氨酰蛋白酶β位点附近，并且在体外导致淀粉样肽的形成减少了约40%。A673T替换对阿尔茨海默病的强大保护作用为“减少APP的β裂解可能预防该疾病”这一假说提供了原理性证据。此外，由于A673T等位基因也能预防无阿尔茨海默病的老年人的认知能力下降，这两者可能是通过相同或相似的机制介导的。
The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease(1-4). The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-beta precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease beta-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.