A non-toxic Hsp90 inhibitor protects neurons from Aβ-induced toxicity

https://doi.org/10.1016/j.bmcl.2007.01.017Get rights and content

Abstract

The molecular chaperones have been implicated in numerous neurodegenerative disorders in which the defining pathology is misfolded proteins and the accumulation of protein aggregates. In Alzheimer’s disease, hyperphosphorylation of tau protein results in its dissociation from microtubules and the formation of pathogenic aggregates. An inverse relationship was demonstrated between Hsp90/Hsp70 levels and aggregated tau, suggesting that Hsp90 inhibitors that upregulate these chaperones could provide neuroprotection. We recently identified a small molecule novobiocin analogue, A4 that induces Hsp90 overexpression at low nanomolar concentrations and sought to test its neuroprotective properties. A4 protected neurons against Aβ-induced toxicity at low nanomolar concentrations that paralleled its ability to upregulate Hsp70 expression. A4 exhibited no cytotoxicity in neuronal cells at the highest concentration tested, 10 μM, thus providing a large therapeutic window for neuroprotection. In addition, A4 was transported across BMECs in vitro, suggesting the compound may permeate the blood–brain barrier in vivo. Taken together, these data establish A4, a C-terminal inhibitor of Hsp90, as a potent lead for the development of a novel class of compounds to treat Alzheimer’s disease.

Graphical abstract

The molecular chaperones have been implicated in numerous neurodegenerative disorders in which the defining pathology is misfolded proteins and the accumulation of protein aggregates. In this manuscript we report the first Hsp90 inhibitor that induces heat shock proteins, but exhibits no toxicity. Based on these findings, the molecule was evaluated for its neuroprotective properties against Aβ-induced toxicity of neurons, and demonstrated an EC50 of ∼ 6 nM.

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Acknowledgments

This work was supported by NIH Grants R01CA120458 and U01CA39610 (B.S.J.B.) and ISOA AG027419 and AG12993 (M.L.M.).

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