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
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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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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Figure 3

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Association of brain LRP levels with AD susceptibility. LRP levels were ...
Association of brain LRP levels with AD susceptibility. LRP levels were quantitated by immunoblotting for the 85-kDa light chain of LRP and normalized to actin. (a) Comparison of AD and age-matched normal controls (NC) showed a significant difference in LRP levels (t = 4.884, df = 76, P < 0.0001). Error bars represent SEM. (b) Representative immunoblots containing LRP and actin signals from AD and NC samples are shown. (c) Levels of LRP in the brain are inversely correlated with age of control subjects (control subjects lacking APOE ε4 allele shown: r = –0.6758, P < 0.0001; all control subjects: r = 0.4905, P = 0.0015). (d) AD patients show a positive correlation between LRP levels and ages at onset of disease (AD subjects lacking APOE ε4 allele shown: r = 0.6048, P = 0.0116; all AD subjects: r = 0.33465, P = 0.0429). The regression slope (center line) and 95% confidence interval (two curved lines) are shown. The correlation coefficient (r) and P values are shown above the graph.