Identification of Alzheimer disease-associated variants in genes that regulate retromer function

Abstract The proteolytic processing of amyloid precursor protein (APP) to generate the neurotoxic amyloid β (Aβ) peptide is central to the pathogenesis of Alzheimer disease (AD). The endocytic system mediates the processing of APP by controlling its access to secretases that cleave APP. A key mediat...

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Published in:	Neurobiology of aging Vol. 33; no. 9; pp. 2231.e15 - 2231.e30
Main Authors:	Vardarajan, Badri N, Bruesegem, Sophia Y, Harbour, Michael E, George-Hyslop, Peter St, Seaman, Matthew N.J, Farrer, Lindsay A
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-09-2012
Subjects:	Aged Aged, 80 and over Aging Alzheimer disease Alzheimer Disease - genetics Black or African American - genetics Cell Line Databases, Genetic Female Genetic association Genetic Predisposition to Disease - genetics Genetic Variation - genetics Genome-Wide Association Study Green Fluorescent Proteins - genetics Green Fluorescent Proteins - metabolism Humans Immunoprecipitation Internal Medicine Israel - ethnology KIAA1033 Male Models, Molecular Neurology rab GTP-Binding Proteins - genetics rab7 GTP-Binding Proteins Rab7A Retromer Risk Factors RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Snx1 Snx3 Sorting Nexins - genetics Transfection Vesicular Transport Proteins - genetics White People - genetics Israel Snx3 Snx1 Alzheimer disease KIAA1033 Genetic association Rab7A Retromer
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Summary:	Abstract The proteolytic processing of amyloid precursor protein (APP) to generate the neurotoxic amyloid β (Aβ) peptide is central to the pathogenesis of Alzheimer disease (AD). The endocytic system mediates the processing of APP by controlling its access to secretases that cleave APP. A key mediator of APP localization is SorL1—a membrane protein that has been genetically linked to AD. The retromer complex is a conserved protein complex required for endosome-to-Golgi retrieval of a number of physiologically important membrane proteins including SorL1. Based on the prior suggestion that endocytosis and retromer sorting pathways might be involved, we hypothesized that variants in other genes in this pathway might also modulate AD risk. Genetic association of AD with 451 polymorphisms in 15 genes encoding retromer or retromer-associated proteins was tested in a Caucasian sample of 8309 AD cases and 7366 cognitively normal elders using individual single nucleotide polymorphism (SNP)- and gene-based tests. We obtained significant evidence of association with KIAA1033 (VEGAS p = 0.025), SNX1 (VEGAS p = 0.035), SNX3 ( p = 0.0057), and RAB7A (VEGAS p = 0.018). Ten KIAA1033 SNPs were also significantly associated with AD in a group of African Americans (513 AD cases, 504 control subjects). Findings with four significant SNX3 SNPs in the discovery sample were replicated in a community-based sample of Israeli-Arabs (124 AD cases, 142 control subjects). We show that Snx3 and Rab7A proteins interact with the cargo-selective retromer complex through independent mechanisms to regulate the membrane association of retromer and thereby are key mediators of retromer function. These data implicate additional AD risk genes in the retromer pathway and formally demonstrate a direct link between the activity of the retromer complex and the pathogenesis of AD.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 contributed equally to this work
ISSN:	0197-4580 1558-1497
DOI:	10.1016/j.neurobiolaging.2012.04.020