Expression of the human ␤-amyloid peptide (A␤) in a transgenic Caenorhabditis elegans Alzheimer disease model leads to the induction of HSP-16 proteins, a family of small heat shockinducible proteins homologous to vertebrate ␣B crystallin. These proteins also co-localize and co-immunoprecipitate with A␤ 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

more »

... al function of this interaction between HSP-16 and A␤, 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 A␤ toxicity. Wild type A␤-(1-42), but not A␤ single chain dimer, was observed to become sequestered in HSP-16.2containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and A␤ in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of A␤ 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 A␤ in vitro, with a preferential affinity for oligomeric A␤ species. This interaction between A␤ and HSP-16.2 also influences the formation of A␤ oligomers in in vitro assays. These studies are consistent with a model in which small chaperone proteins reduce A␤ toxicity by interacting directly with the A␤ peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species. . 2 The abbreviations used are: A␤, ␤-amyloid peptide; AD, Alzheimer disease; ER, endoplasmic reticulum; BSA, bovine serum albumin; WT, wild type; PBS, phosphate-buffered saline; BisTris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; IBM, inclusion body myositis; sHSP, small heat shock protein; GFP, green fluorescent protein.