Formation of highly toxic soluble amyloid beta oligomers by the molecular chaperone prefoldin

Masafumi Sakono, Tamotsu Zako, Hiroshi Ueda, Masafumi Yohda, Mizuo Maeda
FEBS Journal 2008, 275 (23): 5982-93
Alzheimer's disease (AD) is a neurological disorder characterized by the presence of amyloid beta (Abeta) peptide fibrils and oligomers in the brain. It has been suggested that soluble Abeta oligomers, rather than Abeta fibrils, contribute to neurodegeneration and dementia due to their higher level of toxicity. Recent studies have shown that Abeta is also generated intracellularly, where it can subsequently accumulate. The observed inhibition of cytosolic proteasome by Abeta suggests that Abeta is located within the cytosolic compartment. To date, although several proteins have been identified that are involved in the formation of soluble Abeta oligomers, none of these have been shown to induce in vitro formation of the high-molecular-mass (> 50 kDa) oligomers found in AD brains. Here, we examine the effects of the jellyfish-shaped molecular chaperone prefoldin (PFD) on Abeta(1-42) peptide aggregation in vitro. PFD is thought to play a general role in de novo protein folding in archaea, and in the biogenesis of actin, tubulin and possibly other proteins in the cytosol of eukaryotes. We found that recombinant Pyrococcus PFD produced high-molecular-mass (50-250 kDa) soluble Abeta oligomers, as opposed to Abeta fibrils. We also demonstrated that the soluble Abeta oligomers were more toxic than Abeta fibrils, and were capable of inducing apoptosis. As Pyrococcus PFD shares high sequence identity to human PFD and the PFD-homolog protein found in human brains, these results suggest that PFD may be involved in the formation of toxic soluble Abeta oligomers in the cytosolic compartment in vivo.

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