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J. Biol. Chem., Vol. 283, Issue 2, 784-791, January 11, 2008

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Suppression of in Vivo β-Amyloid Peptide Toxicity by Overexpression of the HSP-16.2 Small Chaperone Protein^*

From the Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309

Expression of the human β-amyloid peptide (Aβ) 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 B crystallin. These proteins also co-localize and co-immunoprecipitate with Aβ 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 Aβ, 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 Aβ toxicity. Wild type Aβ-(1–42), but not Aβ single chain dimer, was observed to become sequestered in HSP-16.2-containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and Aβ in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of Aβ 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 Aβ in vitro, with a preferential affinity for oligomeric Aβ species. This interaction between Aβ and HSP-16.2 also influences the formation of Aβ oligomers in in vitro assays. These studies are consistent with a model in which small chaperone proteins reduce Aβ toxicity by interacting directly with the Aβ peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species.

Received for publication, April 20, 2007 , and in revised form, November 7, 2007.

^* This work was supported by NIA Grants AG12423 and AG21037 from the National Institutes of Health (to C. D. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Institute for Behavioral Genetics/Integrative Physiology, University of Colorado, Campus Box 447, Boulder, CO 80309. Fax: 303-492-8063; E-mail: linkc{at}colorado.edu.

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