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PMID: 12145324 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 16 ·2002-08-06 ·Pages 10843-8

DeMattos RB, O'dell MA, Parsadanian M, Taylor JW, Harmony JA, Bales KR, Paul SM, Aronow BJ, Holtzman DM

Abstract

Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-beta (Abeta) in vitro. To determine whether endogenous clusterin plays a role in influencing Abeta deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin(-/-) mice. By 12 months of age, PDAPP, clusterin(-/-) mice had similar levels of brain Abeta deposition as did PDAPP, clusterin(+/+) mice. Although Abeta deposition was similar, PDAPP, clusterin(-/-) mice had significantly fewer fibrillar Abeta (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Abeta structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.

MeSH Terms
Alzheimer Disease/metabolism,pathology Amyloid beta-Peptides/metabolism Amyloid beta-Protein Precursor/metabolism Animals Benzothiazoles Brain/metabolism,pathology Clusterin Disease Models, Animal Glycoproteins/genetics,physiology Mice Mice, Knockout Molecular Chaperones/genetics,physiology Neurites/metabolism,pathology Peptide Fragments/metabolism Plaque, Amyloid/metabolism,pathology Thiazoles/metabolism
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Benzothiazoles Clu protein, mouse Clusterin Glycoproteins Molecular Chaperones Peptide Fragments Thiazoles amyloid beta-protein (1-42) thioflavin T
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
DeMattos Ronald B
Center for the Study of Nervous System Injury, Alzheimer's Disease Research Center, and Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, USA.
O'dell Mark A
Parsadanian Maia
Taylor Jennie W
Harmony Judith A K
Bales Kelly R
Paul Steven M
Aronow Bruce J
Holtzman David M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.162228299
Published
2002-08-06
Epub
2002-00-26
Pages
10843-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC125060
Subset
IM
Grants
NIA NIH HHS · P01 AG011355 · United States
NIA NIH HHS · R01 AG013956 · United States
NIA NIH HHS · P50 AG005681 · United States
NIA NIH HHS · AG13956 · United States
NIA NIH HHS · AG11355 · United States
NIA NIH HHS · R37 AG013956 · United States
NIA NIH HHS · AG05681 · United States
External Links
PubMed source DOI: 10.1073/pnas.162228299 PMC Full Text View journal details
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