Annual Report 2012

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Brain Structure, Abeta Metabolism and Behavior in Mice Deficient in Diabetes and Alzheimer's Associated SorCS1

Researchers: 
Funding year(s): 
2010 to 2012
Funding to date: 
$100,000

This is an extension of an earlier grant. 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 also is associated genetically 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-beta peptide (Abeta) and the Abeta 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 SorCS1c-myc in cultured cells caused a reduction ( p0.002) in Abeta generation. Conversely, endogenous murine Abeta40 and Abeta42 levels were increased (Abeta40, p<0.044; Abeta 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 SorCS1c-myc interacts with APP, SorL1 and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1 and SorCS1:Vps35 complexes from the nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49 percent (p<0.009) and total SorL1 protein levels were decreased by 29 percent (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/Abeta disturbance underlying AD and the insulin/glucose disturbance underlying DM.

Within the past five years, late-onset Alzheimer’s disease and Type 2 Diabetes have been independently linked with the gene for a protein called SorCS1. This project’s objective is to build on this early data to first better understand the link between AD and T2D, and second to point to new potential drug targets for treating both AD and T2D.

2012: No Cost Extension

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-beta peptide (Abeta) and the Abeta 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 SorCS1c-myc in cultured cells caused a reduction ( p0.002) in Abeta generation. Conversely, endogenous murine Abeta40 and Abeta42 levels were increased (Abeta40 , p<0.044; Abeta 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 APPmetabolism,we investigated the possibility that SorCS1c-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from non transgenic 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/Abeta disturbance underlying AD and the insulin/glucose disturbance underlying DM.