Modulation of amyloid β-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway

David E. Kang, Claus U. Pietrzik, Larry Baum, Nathalie Chevallier, David E. Merriam, Maria Z. Kounnas, Steven L. Wagner, Juan C. Troncoso, Claudia H. Kawas, Robert Katzman, Edward H. Koo

Research output: Contribution to journalArticle

Abstract

Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and α2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid β-protein (Aβ). We demonstrate in vitro that LRP mediates the clearance of both Aβ40 and Aβ42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Aβ levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Aβ, this work provides the first in vivo evidence that the LRP pathway may modulate Aβ deposition and AD susceptibility by regulating the removal of soluble Aβ.

Original languageEnglish (US)
Pages (from-to)1159-1166
Number of pages8
JournalJournal of Clinical Investigation
Volume106
Issue number9
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Medicine(all)

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    Kang, D. E., Pietrzik, C. U., Baum, L., Chevallier, N., Merriam, D. E., Kounnas, M. Z., Wagner, S. L., Troncoso, J. C., Kawas, C. H., Katzman, R., & Koo, E. H. (2000). Modulation of amyloid β-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway. Journal of Clinical Investigation, 106(9), 1159-1166. https://doi.org/10.1172/JCI11013