Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population
Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population
复制标题
DOI：
10.1016/j.neurobiolaging.2012.09.017
复制
发表时间：
2013-05-01
影响因子：
4.2
通讯作者：
Tienari, Pentti J.
中科院分区：
文献类型：
--
作者：
Kero, Mia;Paetau, Anders;Tienari, Pentti J.
导致早发性阿尔茨海默病（AD）的APP基因的致病性突变已经被知道超过20年。最近，人们发现APP突变也可能具有保护作用。据报道，一种罕见的变异A673 T可预防AD和年龄相关的认知障碍，并可能在功能上抑制APP的β-分泌酶位点的蛋白水解裂解。我们对515名85岁或以上芬兰受试者的基于人群的样本中APP外显子16进行了测序。274例患者有神经病理学数据。我们在1例受试者（0.2%）中发现了A673 T变异体，该受试者活到104.8岁（队列中第二高的死亡年龄）。神经病理学分析显示几乎没有β-淀粉样蛋白病理学（建立阿尔茨海默病登记协会评分0）。在脑膜动脉中检测到一些血管淀粉样蛋白，表明血管β淀粉样蛋白积聚可能比实质受到更少的抑制。她在104岁时患上了痴呆症，很可能是因为海马硬化症。在104.8岁时实质β-淀粉样蛋白病理学的低量支持A673 T变体保护大脑免受β-淀粉样蛋白病理学和AD的概念。(C)2013 Elsevier Inc. All rights reserved.
Pathogenic mutations of the APP gene, leading to early-onset Alzheimer's disease (AD) have been known for more than 20 years. Recently, it was discovered that APP mutations might also be protective. A rare variant A673T reportedly protects against AD and age-related cognitive impairment and might functionally inhibit proteolytic cleavage at the beta-secretase site of APP. We sequenced APP exon 16 in a population-based sample of 515 Finnish subjects aged 85 or older. Neuropathologic data were available in 274. We found the A673T variant in 1 subject (0.2%), who lived until age 104.8 years (second highest age-at-death in the cohort). Neuropathologic analysis showed little beta-amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease score 0). Some vascular amyloid was detected in meningeal arteries suggesting that vascular beta-amyloid accumulation might be less inhibited than the parenchymal. She was demented at the age of 104, most likely because of hippocampal sclerosis. The low amount of parenchymal beta-amyloid pathology at the age of 104.8 years supports the concept that the A673T variant protects the brain against beta-amyloid pathology and AD. (C) 2013 Elsevier Inc. All rights reserved.