Cell Line Specific Modulation of Extracellular Aβ42 by Hsp40

Heat shock proteins (Hsps) are a set of molecular chaperones involved in cellular repair. They provide protective mechanisms that allow cells to survive potentially lethal insults, In response to a conditioning stress their expression is increased. Here we examined the connection between Hsps and A beta(42), the amyloid peptide involved in the pathological sequence of Alzheimer's disease (AD). Extracellular A beta(42) associates with neuronal cells and is a major constituent of senile plaques, one of the hallmarks of AD. Although Hsps are generally thought to prevent accumulation of misfolded proteins, there is a lack of mechanistic evidence that heat shock chaperones directly modulate A beta(42) toxicity. In this study we show that neither extracellular A beta(42) nor A beta(42)/PrPC trigger the heat shock response in neurons. To address the influence of the neuroprotective heat shock response on cellular A beta(42), Western analysis of A beta(42) was performed following external A beta(42) application. Five hours after a conditioning heat shock, A beta(42) association with CAD cells was increased compared to control neurons. However, at forty-eight hours following heat shock A beta(42) levels were reduced compared to that found for control cells. Moreover, transient transfection of the stress induced Hsp40, decreased CAD levels of A beta(42). In contrast to CAD cells, hippocampal neurons transfected with Hsp40 retained A beta(42) indicating that Hsp40 modulation of A beta(42) proteostasis is cell specific. Mutation of the conserved HPD motif within Hsp40 significantly reduced the Hsp40-mediated A beta(42) increase in hippocampal cultures indicating the importance of this motif in regulating cellular A beta(42). Our data reveal a biochemical link between Hsp40 expression and A beta(42) proteostasis that is cell specific. Therefore, increasing Hsp40 therapeutically with the intention of interfering with the pathogenic cascade leading to neurodegeneration in AD should be pursued with caution.