阿爾茨海默氏癥通常是在65歲以后被診斷出來,，究竟是什么因素導致了這種疾病的發(fā)生呢,？研究人員在2月出版的《自然—遺傳學》期刊上報告,，對攜帶SORL1基因特別變異的個體來說,，他們發(fā)生遲發(fā)性阿爾茨海默氏癥的風險會適度增加,。如果這一研究在另一個附加研究中被確認,，那么SORL1將是這種最常見性疾病的第二個風險因子,。
在發(fā)展型阿爾茨海默氏癥中，一個關鍵的事件是 A-beta肽在淀粉樣前體蛋白 (APP)中的產生,。A-beta肽會毒害神經細胞,，以前的研究認為它是在這種疾病中觀察到的神經退化的誘發(fā)者。以前的研究還推測,，在取自阿爾茨海默氏癥患者大腦的組織樣品中,，調節(jié)APP向A-beta肽轉化的幾種蛋白質的水平降低了，但并不清楚它們之間的因果關系,。
Peter St. George-Hyslop和同事搜尋了幾個負責編碼 APP處理蛋白質的基因的變型,，這些蛋白質可能與阿爾茨海默氏癥有關聯。通過對來自不同種群背景的6組人群的分析,，他們在SORL1基因中鑒別出兩組變異,，這種變異過多地出現在阿爾茨海默氏癥患者的體內。
除了這些基因數據,，作者還提供初步證據表明,，阿爾茨海默氏癥患者的血細胞中傾向于有較低水平的SORL1，而且實驗顯示,，降低培養(yǎng)液中SORL1的水平能夠促進A-beta肽的產量,，作者由此推測出解釋SORL1變異增加神經性退化風險的一個潛在機理。
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.
