Rogaeva Ekaterina, Meng Yan, Lee Joseph H, Gu Yongjun, Kawarai Toshitaka, Zou Fanggeng, Katayama Taiichi, Baldwin Clinton T, Cheng Rong, Hasegawa Hiroshi, Chen Fusheng, Shibata Nobuto, Lunetta Kathryn L, Pardossi-Piquard Raphaelle, Bohm Christopher, Wakutani Yosuke, Cupples L Adrienne, Cuenco Karen T, Green Robert C, Pinessi Lorenzo, Rainero Innocenzo, Sorbi Sandro, Bruni Amalia, Duara Ranjan, Friedland Robert P, Inzelberg Rivka, Hampe Wolfgang, Bujo Hideaki, Song You-Qiang, Andersen Olav M, Willnow Thomas E, Graff-Radford Neill, Petersen Ronald C, Dickson Dennis, Der Sandy D, Fraser Paul E, Schmitt-Ulms Gerold, Younkin Steven, Mayeux Richard, Farrer Lindsay A, St George-Hyslop Peter
Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department, University of Toronto, Toronto, Ontario, Canada.
Nat Genet. 2007 Feb;39(2):168-77. doi: 10.1038/ng1943. Epub 2007 Jan 14.
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 beta peptide (Abeta) 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 Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.
淀粉样前体蛋白（APP）通过内吞途径从细胞表面的再循环在阿尔茨海默病中淀粉样β肽（Aβ）的产生中起关键作用。我们在此报告，SORL1神经元分选受体中的遗传变异与晚发性阿尔茨海默病相关。这些变异发生在SORL1基因（也称为LR11或SORLA）内至少两个不同的内含子序列簇中，可能调节SORL1的组织特异性表达。我们还表明，SORL1指导APP进入再循环途径，并且当SORL1表达不足时，APP被分选到产生Aβ的区室中。这些数据表明，SORL1表达或功能的遗传或获得性变化在机制上参与了阿尔茨海默病的发生。
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