The Lipoprotein Receptor LR11 Regulates Amyloid β Production and Amyloid Precursor Protein Traffic in Endosomal Compartments

• Type of Material: Article
• Authors: Katrin Offe, Emory University; Sara E. Dodson, Emory University; James T. Shoemaker, Emory University; Jason Jon Fritz, Emory University; Marla Gearing, Emory University; Allan I Levey, Emory University; James J Lah, Emory University
• Language: English
• Date: 2006-02-01
• Publisher: Society for Neuroscience
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2006 Society for Neuroscience
• Final Published Version (URL): http://dx.crossref.org/10.1523%2FJNEUROSCI.4946-05.2006
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0270-6474
• Volume: 26
• Issue: 5
• Start Page: 1596
• End Page: 1603
• Grant/Funding Information: This work was supported by National Institutes of Health–National Institute on Aging Grants R01 AG024214 and P50 AG025688.; National Institute on Aging : NIA
• Keywords: VPS10; LR11; lipoprotein receptors; amyloid β; endocytic pathway; sorLA; amyloid precursor protein; Alzheimer’s disease
• Research Categories: Health Sciences, General; Biology, Genetics

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological changes, including the deposition of amyloid β (Aβ) in senile plaques. The mechanisms causing the disease and Aβ accumulation are not well understood, but important genetic associations with apolipoprotein E genotype and involvement of lipoprotein receptors have become apparent. LR11 (also known as SorLA), a member of the low-density lipoprotein receptor family, has been identified previously as an altered transcript in microarray analyses of samples from human AD cases. Here, we show neuronal expression of the lipoprotein receptor LR11 in control brain in regions vulnerable to AD neuropathology and marked reduction of LR11 expression in these regions in AD brains before cell death. Overexpression of LR11 drastically reduces levels of extracellular Aβ and also lowers levels of total cellular amyloid precursor protein (APP). LR11 colocalizes with APP and regulates its trafficking in endocytic compartments, which are important intracellular sites for APP processing and Aβ generation. Endogenous LR11 localizes to neuronal multivesicular bodies in both rat and human brain. The robust correlation between reduced LR11 expression and AD neuropathology and its potent effects on extracellular Aβ levels suggest that this neuronal lipoprotein receptor could play an important role in AD pathogenesis.