Low endogenous and chemical induced heat shock protein induction in a 0N3Rtau-expressing Drosophila larval model of Alzheimer's disease

J Alzheimers Dis. 2013;33(4):1117-33. doi: 10.3233/JAD-2012-121534.


Reduction of tau phosphorylation and aggregation by manipulation of heat shock protein (HSP) molecular chaperones has received much attention in attempts to further understand and treat tauopathies such as Alzheimer's disease. We examined whether endogenous HSPs are induced in Drosophila larvae expressing human tau (3R-tau) in motor neurons, and screened several chemical compounds that target the HSP system using medium-throughput behavioral analysis to assay their effects on tau-induced neuronal dysfunction in vivo. Tau-expressing larvae did not show a significant endogenous HSP induction response, whereas robust induction of hsp70 was detectable in a similar larval model of polyglutamine disease. Although pan-neuronal tau expression augmented the induction of hsp70 following heat shock, several candidate HSP inducing compounds induced hsp70 protein in mammalian cells in vitro but did not detectably induce hsp70 mRNA or protein in tau expressing larvae. The hsp90 inhibitors 17-AAG and radicicol nevertheless caused a dose-dependent reduction in total human tau levels in transgenic larvae without specifically altering tau hyperphosphorylated at S396/S404. These and several other HSP modulating compounds also failed to rescue the tau-induced larval locomotion deficit in this model. Tau pathology in tau-expressing larvae, therefore, induces weak de novo HSP expression relative to other neurodegenerative disease models, and unlike these disease models, pharmacological manipulation of the hsp90 pathway does not lead to further induction of the heat shock response. Forthcoming studies investigating the effects of HSP induction on tau-mediated dysfunction/toxicity in such models will require more robust, non-pharmacological (perhaps genetic) means of manipulating the hsp90 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal*
  • Drosophila melanogaster / genetics*
  • Female
  • Gene Expression Regulation, Developmental
  • HSP70 Heat-Shock Proteins / biosynthesis
  • HSP70 Heat-Shock Proteins / genetics*
  • HSP90 Heat-Shock Proteins / biosynthesis
  • HSP90 Heat-Shock Proteins / genetics*
  • Humans
  • Larva / genetics
  • Male
  • tau Proteins / biosynthesis
  • tau Proteins / genetics*


  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • tau Proteins