title: The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.
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.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gu
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.forename: Taiichi
authors.initials: T
authors.lastname: Katayama
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Fusheng
authors.initials: F
authors.lastname: Chen
authors.forename: Nobuto
authors.initials: N
authors.lastname: Shibata
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Pardossi-Piquard
authors.forename: Christopher
authors.initials: C
authors.lastname: Bohm
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Wakutani
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Karen T
authors.initials: KT
authors.lastname: Cuenco
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pinessi
authors.forename: Innocenzo
authors.initials: I
authors.lastname: Rainero
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorbi
authors.forename: Amalia
authors.initials: A
authors.lastname: Bruni
authors.forename: Ranjan
authors.initials: R
authors.lastname: Duara
authors.forename: Robert P
authors.initials: RP
authors.lastname: Friedland
authors.forename: Rivka
authors.initials: R
authors.lastname: Inzelberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hampe
authors.forename: Hideaki
authors.initials: H
authors.lastname: Bujo
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Song
authors.forename: Olav M
authors.initials: OM
authors.lastname: Andersen
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Sandy D
authors.initials: SD
authors.lastname: Der
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.forename: Gerold
authors.initials: G
authors.lastname: Schmitt-Ulms
authors.forename: Steven
authors.initials: S
authors.lastname: Younkin
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007438:Introns; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008957:Models, Genetic; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C102582:SORL1 protein, human; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins