| First Author | Lane RF | Year | 2010 |
| Journal | J Neurosci | Volume | 30 |
| Issue | 39 | Pages | 13110-5 |
| PubMed ID | 20881129 | Mgi Jnum | J:164876 |
| Mgi Id | MGI:4835582 | Doi | 10.1523/JNEUROSCI.3872-10.2010 |
| Citation | Lane RF, et al. (2010) Diabetes-associated SorCS1 regulates Alzheimer's amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex. J Neurosci 30(39):13110-5 |
| abstractText | 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 SorCS1cbeta-myc in cultured cells caused a reduction (p = 0.002) in Abeta generation. Conversely, endogenous murine Abeta(40) and Abeta(42) levels were increased (Abeta(40), 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 SorCS1cbeta-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/Abeta disturbance underlying AD and the insulin/glucose disturbance underlying DM. |
