Document Detail


Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores.
MedLine Citation:
PMID:  12972252     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Although APP mutations associated with inherited forms of Alzheimer's disease (AD) are relatively rare, detailed studies of these mutations may prove critical for gaining important insights into the mechanism(s) and etiology of AD. Here, we present a detailed biophysical characterization of the structural properties of protofibrils formed by the Arctic variant (E22G) of amyloid-beta protein (Abeta40(ARC)) as well as the effect of Abeta40(WT) on the distribution of the protofibrillar species formed by Abeta40(ARC) by characterizing biologically relevant mixtures of both proteins that may mimic the situation in the heterozygous patients. These studies revealed that the Arctic mutation accelerates both Abeta oligomerization and fibrillogenesis in vitro. In addition, Abeta40(ARC) was observed to affect both the morphology and the size distribution of Abeta protofibrils. Electron microscopy examination of the protofibrils formed by Abeta40(ARC) revealed several morphologies, including: (1) relatively compact spherical particles roughly 4-5 nm in diameter; (2) annular pore-like protofibrils; (3) large spherical particles 18-25 nm in diameter; and (4) short filaments with chain-like morphology. Conversion of Abeta40(ARC) protofibrils to fibrils occurred more rapidly than protofibrils formed in mixed solutions of Abeta40(WT)/Abeta40(ARC), suggesting that co-incubation of Abeta40(ARC) with Abeta40(WT) leads to kinetic stabilization of Abeta40(ARC) protofibrils. An increase in the ratio of Abeta(WT)/Abeta(MUT(Arctic)), therefore, may result in the accumulation of potential neurotoxic protofibrils and acceleration of disease progression in familial Alzheimer's disease mutation carriers.
Authors:
Hilal A Lashuel; Dean M Hartley; Benjamin M Petre; Joseph S Wall; Martha N Simon; Thomas Walz; Peter T Lansbury
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of molecular biology     Volume:  332     ISSN:  0022-2836     ISO Abbreviation:  J. Mol. Biol.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-09-15     Completed Date:  2003-10-28     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985088R     Medline TA:  J Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  795-808     Citation Subset:  IM    
Affiliation:
Harvard Center for Neurodegeneration and Repair, 65 Landsdowne St., Cambridge, MA 02139, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / genetics,  metabolism
Amyloid beta-Protein / chemistry*,  genetics,  metabolism,  ultrastructure
Animals
Humans
Molecular Weight
Mutation*
Peptide Fragments / chemistry*,  genetics,  metabolism,  ultrastructure
Peptides / chemistry,  genetics,  metabolism
Protein Structure, Quaternary
Ultracentrifugation
Grant Support
ID/Acronym/Agency:
AG08470/AG/NIA NIH HHS; GM62580/GM/NIGMS NIH HHS; P41-RR01777/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid beta-Protein; 0/Peptide Fragments; 0/Peptides; 0/amyloid beta-protein (1-40)

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Novel interactions between the components of human and yeast TFIIA/TBP/DNA complexes.
Next Document:  Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and ar...