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Diabetes-associated SorCS1 regulates Alzheimer's amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex.

SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer's disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SORCS1 is also genetically associated with types 1 and 2 diabetes mellitus (T1DM, T2DM). We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer's amyloid-β peptide (Aβ) and the Aβ precursor protein (APP), to test the hypothesis that Sorcs1 deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1cβ-myc in cultured cells caused a reduction (p = 0.002) in Aβ generation. Conversely, endogenous murine Aβ(40) and Aβ(42) levels were increased (Aβ(40), p = 0.044; Aβ(42), p = 0.007) in the brains of female Sorcs1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SORCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1cβ-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% (p = 0.009) and total SorL1 protein levels were decreased by 29% (p = 0.003) in the brains of female Sorcs1 hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/Aβ disturbance underlying AD and the insulin/glucose disturbance underlying DM.

Pubmed ID: 20881129


  • Lane RF
  • Raines SM
  • Steele JW
  • Ehrlich ME
  • Lah JA
  • Small SA
  • Tanzi RE
  • Attie AD
  • Gandy S


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

September 29, 2010

Associated Grants

  • Agency: NCRR NIH HHS, Id: 1 S10 RR0 9145-01
  • Agency: NCI NIH HHS, Id: 5R24 CA095823-04
  • Agency: NIDDK NIH HHS, Id: DK58037
  • Agency: NIA NIH HHS, Id: P01 AG010491
  • Agency: NIA NIH HHS, Id: P01 AG010491-12
  • Agency: NIA NIH HHS, Id: P01 AG010491-120004
  • Agency: NIA NIH HHS, Id: P01 AG010491-13
  • Agency: NIA NIH HHS, Id: P01 AG010491-130004
  • Agency: NIA NIH HHS, Id: P01 AG010491-14
  • Agency: NIA NIH HHS, Id: P01 AG010491-140004
  • Agency: NIA NIH HHS, Id: P01AG10491
  • Agency: NIA NIH HHS, Id: P50 AG005138
  • Agency: NIA NIH HHS, Id: P50 AG008702
  • Agency: NINDS NIH HHS, Id: R01 NS075685
  • Agency: NIGMS NIH HHS, Id: T32GM06754

Mesh Terms

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Animals
  • Cell Line
  • Diabetes Mellitus, Type 2
  • Disease Models, Animal
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Macromolecular Substances
  • Male
  • Membrane Transport Proteins
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Cell Surface
  • Receptors, LDL
  • Vesicular Transport Proteins