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PMID: 11067868 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of clinical investigation ·Vol. 106 ·No. 9 ·2000-11-00 ·Pages 1159-66

Kang DE, Pietrzik CU, Baum L, Chevallier N, Merriam DE, Kounnas MZ, Wagner SL, Troncoso JC, Kawas CH, Katzman R, Koo EH

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 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.

MeSH Terms
Adult Aged Aged, 80 and over Alzheimer Disease/etiology,genetics,metabolism Amyloid beta-Peptides/metabolism Animals Biological Transport, Active Case-Control Studies Cell Line Humans Low Density Lipoprotein Receptor-Related Protein-1 Mice Mice, Knockout Middle Aged Peptide Fragments/metabolism Receptors, Immunologic/genetics,metabolism Receptors, LDL/genetics,metabolism Solubility
Chemicals
Amyloid beta-Peptides Low Density Lipoprotein Receptor-Related Protein-1 Peptide Fragments Receptors, Immunologic Receptors, LDL amyloid beta-protein (1-40) amyloid beta-protein (1-42)
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kang D E
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
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
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43 references, click to expand
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI11013
Published
2000-11-00
Pages
1159-66
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC301422
Subset
IM
Grants
NIA NIH HHS · R01 AG012376 · United States
NIA NIH HHS · AG12376 · United States
NINDS NIH HHS · NS-01812 · United States
External Links
PubMed source DOI: 10.1172/JCI11013 PMC Full Text View journal details
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