Small heat shock proteins inhibit amyloid-β protein aggregation and cerebrovascular amyloid-β protein toxicity

Small heat shock proteins Hsp20 and HspB2/B3 co-localize with Aβ deposition in senile plaques and cerebral amyloid angiopathy in Alzheimer's disease brains, respectively. It was the aim of our study to investigate if these and other sHsps bind to wild-type Aβ1–42 or the more toxic Aβ1–40 carrying the ‘Dutch’ mutation (22Glu → Gln) (D-Aβ1–40), affect Aβ aggregation and thereby influence Aβ cytotoxicity. Binding affinity between sHsps and Aβ was investigated by surface plasmon resonance. Aβ aggregation was studied by using circular dichroism spectroscopy and electron microscopy. Furthermore, we used cultured cerebrovascular cells to investigate the effects of sHsps on Aβ-mediated cytotoxicity. Hsp20, Hsp27 and αB-crystallin, but not HspB2/B3, bound to Aβ (both D-Aβ1–40 and Aβ1–42) and reduced or completely inhibited aggregation of D-Aβ1–40 into mature fibrils but did not affect Aβ1–42 aggregation. Furthermore, these sHsps were effective inhibitors of the cerebrovascular toxicity of Aβ (both D-Aβ1–40 and Aβ1–42) in vitro. Binding affinity of the sHsps to D-Aβ1–40 correlated to the degree of inhibition of Aβ-mediated cytotoxicity and the potential to reduce Aβ β-sheet and fibril formation. With Aβ1–42, a similar correlation between binding affinity and cytotoxicity was observed, but not with its aggregation state. In conclusion, sHsps may regulate Aβ aggregation and serve as antagonists of the biological action of Aβ, but the extent of their interaction depends on the type of sHsp and Aβ peptide.