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

• Type of Material: Article
• Authors: Rachel F. Lane, Mount Sinai School of Medicine; Summer M. Raines, University of Wisconsin; John W. Steele, Mount Sinai School of Medicine; Michelle E. Ehrlich, Mount Sinai School of Medicine; James Lah, Emory University; Scott A. Small, Columbia University; Rudolph E. Tanzi, Harvard University; Alan D. Attie, University of Wisconsin; Sam Gandy, Mount Sinai School of Medicine
• Language: English
• Date: 2011-03-16
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: © 2010 the authors
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.3872-10.2010
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 31
• Issue: 11
• Start Page: 13110
• End Page: 13115
• Grant/Funding Information: 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.
• Keywords: Amyloid beta-Peptides; Genetic Predisposition to Disease; Male; Amyloid beta-Protein Precursor; Membrane Transport Proteins; Female; Mice, Transgenic; Receptors, Cell Surface; Cell Line; Receptors, LDL; Macromolecular Substances; Alzheimer Disease; Mice, Knockout; Animals; Disease Models, Animal; Mice; Vesicular Transport Proteins; Diabetes Mellitus, Type 2; Humans
• Research Categories: Chemistry, Biochemistry; Health Sciences, Medicine and Surgery; Biology, Neuroscience

Abstract

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.