RT Journal Article
SR Electronic
T1 Diabetes-Associated SorCS1 Regulates Alzheimer's Amyloid-β Metabolism: Evidence for Involvement of SorL1 and the Retromer Complex
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 13110
OP 13115
DO 10.1523/JNEUROSCI.3872-10.2010
VO 30
IS 39
A1 Rachel F. Lane
A1 Summer M. Raines
A1 John W. Steele
A1 Michelle E. Ehrlich
A1 James A. Lah
A1 Scott A. Small
A1 Rudolph E. Tanzi
A1 Alan D. Attie
A1 Sam Gandy
YR 2010
UL http://www.jneurosci.org/content/30/39/13110.abstract
AB 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 Aβ40 and Aβ42 levels were increased (Aβ40, p = 0.044; Aβ42, 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.