Log in • Subscribe

Cell Line Specific Modulation of Extracellular Aβ42 by Hsp40

By PLoS ONE • on May 30, 2012

by Anna Carnini, Lucas O. M. Scott, Eva Ahrendt, Juliane Proft, Robert J. Winkfein, Sung-Woo Kim, Michael A. Colicos, Janice E. A. Braun

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 Aβ₄₂, the amyloid peptide involved in the pathological sequence of Alzheimer’s disease (AD)_. Extracellular Aβ₄₂ 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 Aβ₄₂ toxicity. In this study we show that neither extracellular Aβ₄₂ nor Aβ_42/PrP^C trigger the heat shock response in neurons. To address the influence of the neuroprotective heat shock response on cellular Aβ₄₂, Western analysis of Aβ₄₂ was performed following external Aβ₄₂ application. Five hours after a conditioning heat shock, Aβ₄₂ association with CAD cells was increased compared to control neurons. However, at forty-eight hours following heat shock Aβ₄₂ levels were reduced compared to that found for control cells. Moreover, transient transfection of the stress induced Hsp40, decreased CAD levels of Aβ₄₂. In contrast to CAD cells, hippocampal neurons transfected with Hsp40 retained Aβ₄₂ indicating that Hsp40 modulation of Aβ₄₂ proteostasis is cell specific. Mutation of the conserved HPD motif within Hsp40 significantly reduced the Hsp40-mediated Aβ₄₂ increase in hippocampal cultures indicating the importance of this motif in regulating cellular Aβ₄₂. Our data reveal a biochemical link between Hsp40 expression and Aβ₄₂ 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.