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Author Notes:

Correspondence should be addressed to Dr. James J. Lah, Center for Neurodegenerative Disease, 615 Michael Street, Suite 505 South, Atlanta, GA 30322. E-mail: jlah@emory.edu

We thank Howard D. Rees and Hong Yi for excellent technical assistance. We thank Drs. H. Bujo, W. J. Schneider, D. Selkoe, and C. Schaller for sharing reagents.

Subjects:

Research Funding:

National Institute on Aging : NIA

This work was supported by National Institutes of Health–National Institute on Aging Grants R01 AG024214 and P50 AG025688.

Keywords:

  • LR11
  • sorLA
  • VPS10
  • lipoprotein receptors
  • amyloid β
  • amyloid precursor protein
  • Alzheimer’s disease
  • endocytic pathway

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

Tools:

Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 26, Number 5

Publisher:

, Pages 1596-1603

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2006 Society for Neuroscience

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