The molecular chaperone αB-crystallin enhances amyloid β neurotoxicity

Amyloid beta (A beta) is a 40- to 42-residue peptide that is implicated in the pathogenesis of Alzheimer's Disease (AD), As a result of conformational changes, A beta assembles into neurotoxic fibrils deposited as 'plaques' in the diseased brain. In AD brains, the small heat shock proteins (sHsps) alpha B-crystallin and Hsp27 occur at increased levels and colocalize with these plaques. In vitro, sHsps act as molecular chaperones that recognize unfolding peptides and prevent their aggregation, The presence of sHsps in AD brains may thus reflect an attempt to prevent amyloid fibril formation and toxicity. Here we report that alpha B-crystallin does indeed prevent in vitro fibril formation of A beta(1-40). However, rather than protecting cultured neurons against A beta(1-40) toxicity, alpha B-crystallin actually increases the toxic effect. This indicates that the interaction of alpha B-crystallin with conformationally altering A beta(1-40) may keep the latter in a nonfibrillar, yet highly toxic form. (C) 1999 Academic Press.