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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

Molecular Psychiatry volume 22, pages 990–1001 (2017)Cite this article

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Abstract

Induction 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.

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Acknowledgements

We thank Drs William E Armstrong (Anatomy & Neuroscience UTHSC) and Melloni Cook (University of Memphis) for valuable inputs, Dr Deborah Young (The University of Auckland, Auckland, New Zealand) for providing constitutively expressed AAVH-HB hsf1 viruses,28 and Tonia Rex (Vanderbilt University) for AAV-shRNA viral vector. This work is supported by NIH grants to F-FL (AG049772-01); DHH (NS091752); MPM (AG040230 & AG041935); GY (GM107469 and AG048410); WL (CA148706); KS (MH105567 and MH102445); and RO (GM107094). DHH also received support from the UTHSC College of Medicine iRISE Pilot Program. Some of the behavioral procedures were conducted at the Neuroscience Institute’s Behavioral Core at UTHSC.

Author contributions

F-FL designed research; BW, YL, LH, JC, JJL, RW, EK, YC and CJ performed research; KS, HC, AP, RSO, WL, GY, MPM, DHH and F-FL analyzed data; RC provided compound and consultation; BW and F-FL wrote the paper.

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  1. J Chen

    Present address: 8Current address: Department of Pharmaceutical Sciences, Chicago State University, College of Pharmacy, Chicago, IL 60628.,

Authors and Affiliations

  1. Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA

    B Wang, J J Li, R Wang, E Kim, Y Chen, K Sakata, H Chen, R S Ostrom & F-F Liao

  2. Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA

    Y Liu, M P McDonald & D H Heck

  3. Department of Anesthesiology, New York University School of Medicine, New York, NY, USA

    L Huang & G Yang

  4. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA

    J Chen & W Li

  5. Department of Brain Ischemia and Neurodegeneration, Institute for Biomedical Research (IIBB-CSIC), Barcelona, Spain

    C Justicia & A Planas

  6. Department of Neurology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA

    M P McDonald

  7. Oncosynergy, Inc, San Francisco, CA, USA

    R Chen

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Correspondence to F-F Liao.

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Wang, B., Liu, Y., Huang, L. et al. A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer’s mouse model via an HSF1-mediated mechanism. Mol Psychiatry 22, 990–1001 (2017). https://doi.org/10.1038/mp.2016.104

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