Human Prefoldin Inhibits Amyloid-β (Aβ) Fibrillation and Contributes to Formation of Nontoxic A/β Aggregates

Amyloid-beta (A beta) peptides represent key players in the pathogenesis of Alzheimer's disease (AD), and mounting evidence indicates that soluble A beta oligomers mediate the toxicity. Prefoldin (PFD) is a molecular chaperone that prevents aggregation of misfolded proteins. Here we investigated the role of PFD in M aggregation. First, we demonstrated that PFD is expressed in mouse brain by Western blotting and immunohistochemistry and found that PFD is upregulated in AD model APP23 transgenic mice. Then we investigated the effect of recombinant human PFD (hPFD) on A beta(1-42) aggregation in vitro and found that hPFD inhibited Afi fibrillation and induced formation of soluble Afi oligomers. Interestingly, cell viability measurements using the 3-(4,5-dirnethyldnazol-2-y1)-2,5-diphenyltetrazoliurn bromide assay showed that A beta oligomers formed by hPFD were 30-40% less toxic to cultured rat pheochromocytoma (PC 12) cells or primary cortical neurons from embryonic CS7BL/6CrSlc mice than previously reported A beta oligomers (formed by archaeal PFD) and A beta fibrils (p < 0.001). Thioflavin T measurements and immunoblotting indicated different structural properties for the different A beta oligomers. Our findings show a relation between cytotoxicity of A beta ofigomers and structure and suggest a possible protective role of PFD in AD.