title: SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk.
abstract: OBJECTIVE
  Sorting mechanisms that cause the amyloid precursor protein (APP) and the β-secretases and γ-secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD.
  
  
  METHODS
  We analyzed the genetic associations between AD and 16 SORCS1-single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation.
  
  
  RESULTS
  Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ-secretase activity and Aβ levels, the suppression of SorCS1 increased γ-secretase processing of APP and the levels of Aβ.
  
  
  CONCLUSIONS
  These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD.
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.forename: Shinya
authors.initials: S
authors.lastname: Tokuhiro
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.forename: Christopher
authors.initials: C
authors.lastname: Conrad
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: Lili-Naz
authors.initials: LN
authors.lastname: Hazrati
authors.forename: András
authors.initials: A
authors.lastname: Palotás
authors.forename: Raphael
authors.initials: R
authors.lastname: Lantigua
authors.forename: Martin
authors.initials: M
authors.lastname: Medrano
authors.forename: Ivonne
authors.initials: I
authors.lastname: Z Jiménez-Velázquez
authors.forename: Badri
authors.initials: B
authors.lastname: Vardarajan
authors.forename: Irene
authors.initials: I
authors.lastname: Simkin
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Peter St
authors.initials: PS
authors.lastname: George-Hyslop
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D015201:Meta-Analysis as Topic; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology*; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D011956:Receptors, Cell Surface; C472780:SORCS1 protein, human; C102582:SORL1 protein, human; D053829:Amyloid Precursor Protein Secretases