%0 Journal Article
%T Cell Line Specific Modulation of Extracellular A¦Â42 by Hsp40
%A Anna Carnini
%A Lucas O. M. Scott
%A Eva Ahrendt
%A Juliane Proft
%A Robert J. Winkfein
%A Sung-Woo Kim
%A Michael A. Colicos
%A Janice E. A. Braun
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0037755
%X 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¦Â42, the amyloid peptide involved in the pathological sequence of Alzheimer¡¯s disease (AD). Extracellular A¦Â42 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¦Â42 toxicity. In this study we show that neither extracellular A¦Â42 nor A¦Â42/PrPC trigger the heat shock response in neurons. To address the influence of the neuroprotective heat shock response on cellular A¦Â42, Western analysis of A¦Â42 was performed following external A¦Â42 application. Five hours after a conditioning heat shock, A¦Â42 association with CAD cells was increased compared to control neurons. However, at forty-eight hours following heat shock A¦Â42 levels were reduced compared to that found for control cells. Moreover, transient transfection of the stress induced Hsp40, decreased CAD levels of A¦Â42. In contrast to CAD cells, hippocampal neurons transfected with Hsp40 retained A¦Â42 indicating that Hsp40 modulation of A¦Â42 proteostasis is cell specific. Mutation of the conserved HPD motif within Hsp40 significantly reduced the Hsp40-mediated A¦Â42 increase in hippocampal cultures indicating the importance of this motif in regulating cellular A¦Â42. Our data reveal a biochemical link between Hsp40 expression and A¦Â42 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0037755