title: Suppression of in vivo beta-amyloid peptide toxicity by overexpression of the HSP-16.2 small chaperone protein.
abstract: Expression of the human beta-amyloid peptide (Abeta) in a transgenic Caenorhabditis elegans Alzheimer disease model leads to the induction of HSP-16 proteins, a family of small heat shock-inducible proteins homologous to vertebrate alphaB crystallin. These proteins also co-localize and co-immunoprecipitate with Abeta in this model (Fonte, V., Kapulkin, V., Taft, A., Fluet, A., Friedman, D., and Link, C. D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 9439-9444). To investigate the molecular basis and biological function of this interaction between HSP-16 and Abeta, we generated transgenic C. elegans animals with high level, constitutive expression of HSP-16.2. We find that constitutive expression of wild type, but not mutant, HSP-16.2 partially suppresses Abeta toxicity. Wild type Abeta-(1-42), but not Abeta single chain dimer, was observed to become sequestered in HSP-16.2-containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and Abeta in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of Abeta peptide or alter the pattern of the predominant oligomeric species. Studies with recombinant HSP-16.2 demonstrated that HSP-16.2 can bind directly to Abeta in vitro, with a preferential affinity for oligomeric Abeta species. This interaction between Abeta and HSP-16.2 also influences the formation of Abeta oligomers in in vitro assays. These studies are consistent with a model in which small chaperone proteins reduce Abeta toxicity by interacting directly with the Abeta peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Fonte
authors.forename: D Randal
authors.initials: DR
authors.lastname: Kipp
authors.forename: John
authors.initials: J
authors.lastname: Yerg
authors.forename: David
authors.initials: D
authors.lastname: Merin
authors.forename: Margaret
authors.initials: M
authors.lastname: Forrestal
authors.forename: Eileen
authors.initials: E
authors.lastname: Wagner
authors.forename: Christine M
authors.initials: CM
authors.lastname: Roberts
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Link
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D017124:Conserved Sequence; D004195:Disease Models, Animal; D006360:Heat-Shock Proteins / Q000235:genetics*; D050888:Heat-Shock Proteins, Small / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; C525841:HSPB11 protein, human; D006360:Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D047908:Intracellular Signaling Peptides and Proteins