Interaction of intracellular β amyloid peptide with chaperone proteins

Expression of the human beta amyloid peptide (Abeta) in transgenic Caenorhabditis elegans animals can lead to the formation of intracellular immunoreactive deposits as well as the formation of intracellular amyloid. We have used this model to identify proteins that interact with intracellular Abeta in vivo. Mass spectrometry analysis of proteins that specifically coinimunoprecipitate with Abeta has identified six likely chaperone proteins: two members of the HSP70 family, three alphaB-crystallin-related small heat shock proteins (HSP-16s), and a putative ortholog of a mammalian small glutamine-rich tetratricopeptide repeat-containing protein proposed to regulate HSP70 function. Quantitative reverse transcription-PCR analysis shows that the small heat shock proteins are also transcriptionally induced by Abeta expression. Immunohistochemistry demonstrates that HSP-16 protein closely colocalizes with intracellular Abeta in this model. Transgenic animals expressing a nonaggregating Abeta variant, a single-chain Abeta dimer, show an altered pattern of coimmunoprecipitating proteins and an altered cellular distribution of HSP-16. Double-stranded RNA inhibition of R05F9.10, the putative C elegans ortholog of the human small glutamine-rich tetratricopeptide-repeat-containing protein (SGT), results in suppression of toxicity associated with Abeta expression. These results suggest that chaperone function can play a role in modulating intracellular Abeta metabolism and toxicity.