Type 2 diabetes mellitus (T2D or T2DM) increases the risk for Alzheimer's disease (AD), and SORCS1 is genetically linked to both T2D and AD. We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer's amyloid-? (??) precursor protein (APP), in order to define the molecular mechanisms underlying this coordinate genetic linkage to both diseases. Overexpression of SorCS1c?-myc in cultured cells caused a reduction (p=0.002) in ?? generation (Lane et al., 2010). Endogenous murine A?40 and ??42 levels were increased (A?40, p=0.044;A?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, another AD-linked Vps10-domain protein, directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1c?-myc might interact 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-/- mice. We hypothesize that dysfunction of SorCS1 may contribute to both the APP/?? disturbance underlying AD and the insulin/glucose metabolism disturbance underlying DM. In order to test this hypothesis further, we propose the following specific aims:
Specific Aim 1. To evaluate the importance of SorCS1 protein interaction motifs and SorCS1/SorL1/APP complex formation on APP metabolism by: (a) Characterizing APP metabolism in cultured cells overexpressing SorCS1;(b) Testing the effects of mutations of protein-protein interacting motifs in the cytoplasmic and ectodomains of SorCS1 on both the formation of tripartite SorCS1/SorL1/APP complexes and APP metabolism;(c) Testing the effect of a putative pathogenic SorCS1 polymorphism on both the formation of tripartite SorCS1/SorL1/APP complexes and APP metabolism;(d) Confirming the importance of functional domains identified in Aim 1aii and 1aiii by viral gene transfer into primary cultures.
Specific Aim 2. To employ Sorcs1 hypomorphic and plaque- forming human Swedish APP/PS bigenic mice crossed with Sorcs1 hypomorphic mice for characterization of: (i) endogenous APP metabolism;(ii) hippocampal morphometry, dendritic arborization, and spine structure;(c) learning behavior. Aging (3 mo, 6 mo, 12 mo) effects will also be studied.
Specific Aim 3. To perform standard glucose and insulin tolerance tests and metabolic profile phenotyping of Sorcs1-/- mice and plaque-forming" human Swedish APP/PS co-transgenic mice crossed with Sorcs1 -/- mice.
Type 2 diabetes mellitus (T2DM) increases the risk for Alzheimer's disease (AD). Both diseases are highly complex, and several mechanisms have been proposed for this association, including hypercholesterolemia, vasculopathic factors, and insulin resistance, among others. We sought and identified a genetic factor, SORCS1, that is an excellent candidate for modulation of a coordinated risk for both diseases, and we now propose to work out mechanistic details for how SorCS1 controls risk for AD and T2DM.
|Knight, Elysse M; Ruiz, Henry H; Kim, Soong Ho et al. (2016) Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer's APP/PSEN1 mice by gene targeting of diabetes/Alzheimer's-related Sorcs1. Acta Neuropathol Commun 4:16|
|Ruiz, Henry H; Chi, Tiffany; Shin, Andrew C et al. (2016) Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimers Dement 12:851-61|
|Readhead, B; Haure-Mirande, J-V; Zhang, B et al. (2016) Molecular systems evaluation of oligomerogenic APP(E693Q) and fibrillogenic APP(KM670/671NL)/PSEN1(Î”exon9) mouse models identifies shared features with human Alzheimer's brain molecular pathology. Mol Psychiatry 21:1099-111|
|(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Stoeckel, Luke E; Arvanitakis, Zoe; Gandy, Sam et al. (2016) Complex mechanisms linking neurocognitive dysfunctionÂ to insulin resistance and other metabolic dysfunction. F1000Res 5:353|
|Brautigam, Hannah; Moreno, Cesar L; Steele, John W et al. (2015) Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1-/- phenotype and forms complexes with wildtype PS1 and nicastrin. Sci Rep 5:17042|
|Zhu, Li; Zhong, Minghao; Elder, Gregory A et al. (2015) Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A 112:11965-70|
|Gandy, Sam; Sano, Mary (2015) Alzheimer disease: Solanezumab-prospects for meaningful interventions in AD? Nat Rev Neurol 11:669-70|
|Gandy, Sam; Haroutunian, Vahram; DeKosky, Steven T et al. (2013) CR1 and the "vanishing amyloid" hypothesis of Alzheimer's disease. Biol Psychiatry 73:393-5|
|Lane, Rachel F; Steele, John W; Cai, Dongming et al. (2013) Protein sorting motifs in the cytoplasmic tail of SorCS1 control generation of Alzheimer's amyloid-Î² peptide. J Neurosci 33:7099-107|
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