Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway.
Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha2M, 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 beta-protein (Abeta). We demonstrate in vitro that LRP mediates the clearance of both Abeta40 and Abeta42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Abeta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Abeta, this work provides the first in vivo evidence that the LRP pathway may modulate Abeta deposition and AD susceptibility by regulating the removal of soluble Abeta.
Kang
D E
DE
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
Pietrzik
C U
CU
Baum
L
L
Chevallier
N
N
Merriam
D E
DE
Kounnas
M Z
MZ
Wagner
S L
SL
Troncoso
J C
JC
Kawas
C H
CH
Katzman
R
R
Koo
E H
EH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D016022:Case-Control Studies; D002460:Cell Line; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D011973:Receptors, LDL; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)