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 Aβ(42), the amyloid peptide involved in the pathological sequence of Alzheimer's disease (AD). Extracellular Aβ(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 Aβ(42) toxicity. In this study we show that neither extracellular Aβ(42) nor Aβ(42/)PrP(C) trigger the heat shock response in neurons. To address the influence of the neuroprotective heat shock response on cellular Aβ(42), Western analysis of Aβ(42) was performed following external Aβ(42) application. Five hours after a conditioning heat shock, Aβ(42) association with CAD cells was increased compared to control neurons. However, at forty-eight hours following heat shock Aβ(42) levels were reduced compared to that found for control cells. Moreover, transient transfection of the stress induced Hsp40, decreased CAD levels of Aβ(42). In contrast to CAD cells, hippocampal neurons transfected with Hsp40 retained Aβ(42) indicating that Hsp40 modulation of Aβ(42) proteostasis is cell specific. Mutation of the conserved HPD motif within Hsp40 significantly reduced the Hsp40-mediated Aβ(42) increase in hippocampal cultures indicating the importance of this motif in regulating cellular Aβ(42). Our data reveal a biochemical link between Hsp40 expression and Aβ(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.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Anna
A
Carnini
Lucas O M
LO
Scott
Eva
E
Ahrendt
Juliane
J
Proft
Robert J
RJ
Winkfein
Sung-Woo
SW
Kim
Michael A
MA
Colicos
Janice E A
JE
Braun
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism*; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007700:Kinetics; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D011328:Prions / Q000378:metabolism; D051381:Rats
D016229:Amyloid beta-Peptides; D050956:HSP40 Heat-Shock Proteins; D010446:Peptide Fragments; D011328:Prions; C075222:amyloid beta-protein (1-42)