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

B. Wang; Y. Liu; L. Huang; J. Chen; J. J. Li; R. Wang; E. Kim; Y. Chen; C. Justicia; K. Sakata; H. Chen; A. Planas; R. S. Ostrom; W. Li; G. Yang; M. P. McDonald; R. Chen; D. H. Heck; F. F. Liao

doi:10.1038/mp.2016.104

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

B. Wang, Y. Liu, L. Huang, J. Chen, J. J. Li, R. Wang, E. Kim, Y. Chen, C. Justicia, K. Sakata, H. Chen, A. Planas, R. S. Ostrom, W. Li, G. Yang, M. P. McDonald, R. Chen, D. H. Heck, F. F. Liao

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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.

Original language	English (US)
Pages (from-to)	990-1001
Number of pages	12
Journal	Molecular psychiatry
Volume	22
Issue number	7
DOIs	https://doi.org/10.1038/mp.2016.104
State	Published - Jul 1 2017
Externally published	Yes

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Publisher Copyright:
© 2017 Macmillan Publishers Limited.

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Wang, B., Liu, Y., Huang, L., Chen, J., Li, J. J., Wang, R., Kim, E., Chen, Y., Justicia, C., Sakata, K., Chen, H., Planas, A., Ostrom, R. S., Li, W., Yang, G., McDonald, M. P., Chen, R., Heck, D. H., & Liao, F. F. (2017). 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, 22(7), 990-1001. https://doi.org/10.1038/mp.2016.104

Wang, B, Liu, Y, Huang, L, Chen, J, Li, JJ, Wang, R, Kim, E, Chen, Y, Justicia, C, Sakata, K, Chen, H, Planas, A, Ostrom, RS, Li, W, Yang, G, McDonald, MP, Chen, R, Heck, DH & Liao, FF 2017, '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, vol. 22, no. 7, pp. 990-1001. https://doi.org/10.1038/mp.2016.104

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

Abstract

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