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Author Notes:

Dr. Sam Gandy, Departments of Neurology and Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1137, New York, NY 10029. E-mail: samuel.gandy@mssm.edu.

R.F.L. and S.M.R. contributed equally to this work.

We thank Efrat Levy (New York University);Gopal Thinakaran (University of Chicago); and Nabil Seidah (Clinical Research Institute, Montreal) for cDNA constructs.


Research Funding:

This work was supported by National Institute on Aging Grant P01AG10491 (to S.G.); Veterans Affairs Merit Review Grant 1I01BX000348 (S.G.); and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK58037 (A.D.A.).

S.G. and R.E.T. are members of the Cure Alzheimer's Fund (CAF) Research Consortium and acknowledge the support of CAF.

Confocal laser scanning microscopy was performed at the Mount Sinai School of Medicine-Microscopy Shared Resource Facility, supported with funding from a National Institutes of Health (NIH)–National Cancer Institute Shared Resources Grant (5R24 CA095823-04); a National Science Foundation Major Research Instrumentation Grant (DBI-9724504); and an NIH Shared Instrumentation Grant (1 S10 RR0 9145-01).

J.W.S. is a trainee in the Integrated Pharmacological Sciences Training Program supported by Grant T32GM06754 from the National Institute of General Medical Sciences.


  • 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

Diabetes-associated SorCS1 regulates Alzheimer's amyloid-β metabolism: Evidence for involvement of SorL1 and the retromer complex (Journal of Neuroscience (2010) (13110-13115))


Journal Title:

Journal of Neuroscience Nursing


Volume 31, Number 11


, Pages 13110-13115

Type of Work:

Article | Final Publisher PDF


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.

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© 2010 the authors

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