Article

Diabetes-Associated SorCS1 Regulates Alzheimer's Amyloid- Metabolism: Evidence for Involvement of SorL1 and the Retromer Complex

Department of Neurology and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2010; 30(39):13110-5. DOI: 10.1523/JNEUROSCI.3872-10.2010
Source: PubMed

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.

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Available from: James J Lah, Jan 27, 2014
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    • "These included the synaptic adhesion molecules Nlgn1 and Nlgn3 (Figure 4C, 4D, and S4A; Table S2), and the AMPAR subunit Gria2 (GluA2) (Figure 4C and S4A; Table S2). Various other receptors were also present, including members of the Plexin semaphorin receptor family, the previously identified SorCS1 interactor amyloid precursor protein (APP) (Lane et al., 2010), and Ntrk2 (TrkB), the receptor for the neurotrophin BDNF (Table S2). The results from the SorCS1 ectodomain interactome analysis suggest that SorCS1 interacts with multiple receptors and may regulate key synaptic functions. "
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    • "Certain IDE genotypes are related to a higher risk of diabetes (Fakhrai-Rad et al., 2000; Karamohamed et al., 2003; Kwak et al., 2008; Rudovich et al., 2009), although the contribution of IDE to diabetes is controversial (Groves et al., 2003) and other studies have found no relationship (Florez et al., 2006; Qin and Jia, 2008). SORCS1 may also affect insulin levels and the risk of diabetes (Clee et al., 2006; Goodarzi et al., 2007; Lane et al., 2010). Diabetes and insulin resistance are also more prevalent in persons with Down syndrome (Fonseca et al., 2005). "
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    • "Certain IDE genotypes are related to a higher risk of diabetes (Fakhrai-Rad et al., 2000; Karamohamed et al., 2003; Kwak et al., 2008; Rudovich et al., 2009), although the contribution of IDE to diabetes is controversial (Groves et al., 2003) and other studies have found no relationship (Florez et al., 2006; Qin and Jia, 2008). SORCS1 may also affect insulin levels and the risk of diabetes (Clee et al., 2006; Goodarzi et al., 2007; Lane et al., 2010). Diabetes and insulin resistance are also more prevalent in persons with Down syndrome (Fonseca et al., 2005). "

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