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PMID: 17220890 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

Nature genetics ·Vol. 39 ·No. 2 ·2007-02-00 ·Pages 168-77

Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P

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.

MeSH Terms
Age of Onset Alzheimer Disease/genetics Amyloid beta-Peptides/metabolism Amyloid beta-Protein Precursor/metabolism Cell Line Endosomes/metabolism Genetic Variation Haplotypes Humans Introns LDL-Receptor Related Proteins/genetics Membrane Transport Proteins/genetics Models, Genetic Organ Specificity Polymorphism, Single Nucleotide Protease Nexins Receptors, Cell Surface/metabolism Vesicular Transport Proteins/metabolism
Chemicals
APP protein, human Amyloid beta-Peptides Amyloid beta-Protein Precursor LDL-Receptor Related Proteins Membrane Transport Proteins Protease Nexins Receptors, Cell Surface SORL1 protein, human VPS35 protein, human Vesicular Transport Proteins
Authors & Affiliations
41 authors, click to expand affiliations / ORCID
Rogaeva Ekaterina
Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department, University of Toronto, Toronto, Ontario, Canada.
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
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1061-4036
DOI
10.1038/ng1943
Published
2007-02-00
Epub
2007-00-14
Pages
168-77
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2657343
Subset
IM
Grants
NIA NIH HHS · R37 AG015473-09 · United States
NIA NIH HHS · R01-HG/AG02213 · United States
NIA NIH HHS · R01-AG09029 · United States
NIA NIH HHS · R37 AG015473-10 · United States
NIA NIH HHS · R01 AG009029 · United States
NIA NIH HHS · P50 AG016574 · United States
NIA NIH HHS · P01-AG07232 · United States
NIA NIH HHS · R37 AG015473-08 · United States
NIA NIH HHS · P30 AG013846 · United States
NIA NIH HHS · R37 AG015473-06 · United States
NIA NIH HHS · P01 AG007232 · United States
NIA NIH HHS · P50-AG16574 · United States
NIA NIH HHS · R37 AG015473 · United States
NIA NIH HHS · R37-AG15473 · United States
NIA NIH HHS · R01 AG017173 · United States
NIA NIH HHS · R01-AG017173 · United States
NIA NIH HHS · P30-AG13846 · United States
NIA NIH HHS · U01-AG06786 · United States
NIA NIH HHS · U01 AG006786 · United States
NIA NIH HHS · R37 AG015473-07 · United States
External Links
PubMed source DOI: 10.1038/ng1943 PMC Full Text View journal details
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