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The Journal of Neuroscience, February 1, 2006, 26(5):1596-1603; doi:10.1523/JNEUROSCI.4946-05.2006
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Neurobiology of Disease
The Lipoprotein Receptor LR11 Regulates Amyloid  Production and Amyloid Precursor Protein Traffic in Endosomal Compartments
Katrin Offe,1,2
Sara E. Dodson,1,2
James T. Shoemaker,1,4
Jason J. Fritz,1,4
Marla Gearing,1,3
Allan I. Levey,1,4 and
James J. Lah1,4
1Center for Neurodegenerative Disease, 2Graduate Program in Neuroscience, and 3Departments of Pathology and 4Neurology, Emory University, Atlanta, Georgia 30322
Correspondence should be addressed to Dr. James J. Lah, Center for Neurodegenerative Disease, 615 Michael Street, Suite 505 South, Atlanta, GA 30322. Email: jlah{at}emory.edu
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological changes, including the deposition of amyloid  (A) in senile plaques. The mechanisms causing the disease and A 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 A 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 A 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 A levels suggest that this neuronal lipoprotein receptor could play an important role in AD pathogenesis.
Key words: LR11; sorLA; VPS10; lipoprotein receptors; amyloid ; amyloid precursor protein; Alzheimer’s disease; endocytic pathway
Received Sept. 18, 2005;
revised Dec. 16, 2005;
accepted Dec. 19, 2005.
Correspondence should be addressed to Dr. James J. Lah, Center for Neurodegenerative Disease, 615 Michael Street, Suite 505 South, Atlanta, GA 30322. Email: jlah{at}emory.edu
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