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A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism

AuthorsWang, Bin; Liu, Y.; Huang, L.; Chen, J.; Li, Jing Jing; Wang, R.; Kim, E.; Chen, Y.; Justicia, Carles ; Sakata, K.; Chen, H.; Planas, Anna M. ; Ostrom, R. S.; Li, W.; Yang, Guang; McDonald, M. P.; Chen, R.; Heck, D. H.; Liao, F.-F.
Issue Date26-Jul-2016
CitationMolecular Psychiatry 22: 990-1001 (2017)
AbstractInduction of neuroprotective heat-shock proteins via pharmacological Hsp90 inhibitors is currently being investigated as a potential treatment for neurodegenerative diseases. Two major hurdles for therapeutic use of Hsp90 inhibitors are systemic toxicity and limited central nervous system permeability. We demonstrate here that chronic treatment with a proprietary Hsp90 inhibitor compound (OS47720) not only elicits a heat-shock-like response but also offers synaptic protection in symptomatic Tg2576 mice, a model of Alzheimer’s disease, without noticeable systemic toxicity. Despite a short half-life of OS47720 in mouse brain, a single intraperitoneal injection induces rapid and long-lasting (>3 days) nuclear activation of the heat-shock factor, HSF1. Mechanistic study indicates that the remedial effects of OS47720 depend upon HSF1 activation and the subsequent HSF1-mediated transcriptional events on synaptic genes. Taken together, this work reveals a novel role of HSF1 in synaptic function and memory, which likely occurs through modulation of the synaptic transcriptome.
Publisher version (URL)https://doi.org/10.1038/mp.2016.104
Appears in Collections:(IIBB) Artículos
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