Low Endogenous and Chemical Induced Heat Shock Protein Induction in a 0N3Rtau-Expressing Drosophila Larval Model of Alzheimer's Disease

Abstract

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.

Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease

“…This shows proof of concept that targeting Hsp90 co-chaperones can lead to more potent and specific outcomes. Similarly, Withaferin A treatment induces Hsp70 and Hsp27 expression, but was also shown to lessen tau aggregate burden in a mouse model of tauopathies 82 .…”

“…This suggests that targeting major pathways in the cell may be tolerable for particular diseases. In the case of Hsp90 inhibitors, the efficacy of this strategy was tested and proven in vivo multiple times 18, 24, 19, 82 , with no signs of overt toxicity. There have been pharmacological issues with some of the Hsp90 inhibitors that are due to their chemical composition rather than their target 125 , and these challenges have dampened enthusiasm for the approach to some extent.…”

Potential synergy between tau aggregation inhibitors and tau chaperone modulators

“…17-AAG was also able to decrease tau in an in vitro model of tauopathy [27]. Although the analog compound was unable to alter tau phosphorylation at serines 396 and 404 or rescue a motor deficit, Sinadinos and colleagues recently showed that treating Drosophila larvae expressing human 3R tau with 17-AAG dramatically decreased total tau levels [28]. …”

“…Radicicol is a natural product that inhibits Hsp90 while inducing Hsp40 and Hsp70. Again in a Drosophila model, radicicol has been shown to dose-dependently decrease the levels of tau [28]. Analogs of radicicol, originally made for use in oncogenic research, have yet to be evaluated for their effects on tau [29].…”

“…This development, however, is in its infancy. Withaferin A, one known inhibitor of the Hsp90 co-chaperone Cdc37, was shown to decrease aggregated tau in a mouse model, but it also led to the induction of Hsp27 and Hsp70 [28]. Other Hsp90 co-chaperones, such as FKBP51 [32] and CHIP [22], have been identified as being good targets for altering tau phosphorylation states and levels.…”