阿尔茨海默氏症通常是在65岁以后被诊断出来，究竟是什么因素导致了这种疾病的发生呢？研究人员在2月出版的《自然—遗传学》期刊上报告，对携带SORL1基因特别变异的个体来说，他们发生迟发性阿尔茨海默氏症的风险会适度增加。如果这一研究在另一个附加研究中被确认，那么SORL1将是这种最常见性疾病的第二个风险因子。
在发展型阿尔茨海默氏症中，一个关键的事件是 A-beta肽在淀粉样前体蛋白 (APP)中的产生。A-beta肽会毒害神经细胞，以前的研究认为它是在这种疾病中观察到的神经退化的诱发者。以前的研究还推测，在取自阿尔茨海默氏症患者大脑的组织样品中，调节APP向A-beta肽转化的几种蛋白质的水平降低了，但并不清楚它们之间的因果关系。
Peter St. George-Hyslop和同事搜寻了几个负责编码 APP处理蛋白质的基因的变型，这些蛋白质可能与阿尔茨海默氏症有关联。通过对来自不同种群背景的6组人群的分析，他们在SORL1基因中鉴别出两组变异，这种变异过多地出现在阿尔茨海默氏症患者的体内。
除了这些基因数据，作者还提供初步证据表明，阿尔茨海默氏症患者的血细胞中倾向于有较低水平的SORL1，而且实验显示，降低培养液中SORL1的水平能够促进A-beta肽的产量，作者由此推测出解释SORL1变异增加神经性退化风险的一个潜在机理。
英文原文摘要：
The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease
Ekaterina Rogaeva, Yan Meng, Joseph H Lee, Yongjun Gu, Toshitaka Kawarai, Fanggeng Zou, Taiichi Katayama1, Clinton T Baldwin, Rong Cheng, Hiroshi Hasegawa, Fusheng Chen1, Nobuto Shibata1, Kathryn L Lunetta, Raphaelle Pardossi-Piquard, Christopher Bohm1, Yosuke Wakutani, L Adrienne Cupples, Karen T Cuenco, Robert C Green, Lorenzo Pinessi, Innocenzo Rainero, Sandro Sorbi, Amalia Bruni, Ranjan Duara8, Robert P Friedland9, Rivka Inzelberg, Wolfgang Hampe, Hideaki Bujo, You-Qiang Song, Olav M Andersen, Thomas E Willnow, Neill Graff-Radford, Ronald C Petersen, Dennis Dickson, Sandy D Der, Paul E Fraser, Gerold Schmitt-Ulms, Steven Younkin, Richard Mayeux, Lindsay A Farrer & Peter St George-Hyslop
The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid peptide (A) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into A-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.
