Modulation of amyloid β-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor–related protein pathway
David E. Kang, … , Robert Katzman, Edward H. Koo
David E. Kang, … , Robert Katzman, Edward H. Koo
Published November 1, 2000
Citation Information: J Clin Invest. 2000;106(9):1159-1166. https://doi.org/10.1172/JCI11013.
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Article

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

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.

Authors

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

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Association of LRP genotypes with LRP levels and amyloid burden in the A...
Association of LRP genotypes with LRP levels and amyloid burden in the AD brain. LRP levels were quantitated by immunoblotting for the 85-kDa light chain of LRP and normalized to actin. (a) AD patients harboring LRP T allele showed significantly higher levels of LRP in the brain (t = 2.335, df = 35, P = 0.0254). (b) AD brains were segregated into ordered categories of increasing amyloid burden, ranging from less than 30, 30–39, 40–49, and greater than 49 plaques per field and examined for association with LRP genotypes. The percentage and number of individuals within each plaque-per-field category are shown as a function of LRP genotypes. Statistical analysis shows an excessive overrepresentation of C/C genotypes across increasing plaques-per-field categories compared with T-positive genotypes (χ2 for linear trend = 11.762, df = 1, P = 0.0006). (c) The LRP effect on amyloid burden is still observed among subjects that do not carry the APOE ε4 allele (χ2 for linear trend = 6.135, df = 1, P = 0.0133).