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The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease |
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| Authors: | 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 |
| Institution: | Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department, University of Toronto, Toronto, Ontario, Canada. |
| Abstract: | 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. |
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