The Neuronal Sortilin-Related Receptor SORL1 Is Genetically Associated With Alzheimer Disease

Nat Genet. 2007 Feb;39(2):168-77. doi: 10.1038/ng1943. Epub 2007 Jan 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • 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