Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers

Abstract Heat shock response, mediated by heat shock proteins, is a highly conserved physiological process in multicellular organisms for reestablishment of cellular homeostasis. Expression of heat shock factors and subsequent heat shock protein plays a role in protection against proteotoxicity in invertebrate and vertebrate models. Proteotoxicity due to β-amyloid peptide (Aβ) oligomerization has been linked to the pathogenesis of Alzheimer's disease. Previously, we demonstrated that progressive paralysis induced by expression of human Aβ 1–42 in transgenic Caenorhabditis elegans was alleviated by Aβ oligomer inhibitors Ginkgo biloba extract and its constituents [Wu, Y., Wu, Z., Butko, P., Christen, Y., Lambert, M.P., Klein, W.L., Link, C.D., Luo, Y., 2006. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans . J. Neurosci. 26(50): 13102–13113]. In this study, we apply a protective heat shock to the transgenic C. elegans and demonstrate: (1) a delay in paralysis, (2) increased expression of small heat shock protein HSP16.2, and (3) significant reduction of Aβ oligomers in a heat shock time-dependent manner. These results suggest that transient heat shock lessens Aβ toxicity by diminishing Aβ oligomerization, which provides a link between up regulation of endogenous chaperone proteins and protection against Aβ proteotoxicity in vivo .