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

Bin Wang, Yu Liu, L. Huang, J. Chen, J. J. Li, R. Wang, E. Kim, Y. Chen, C. Justicia, Kazuko Sakata, Hao Chen, A. Planas, R. S. Ostrom, W. Li, G. Yang, Michael Mcdonald, R. Chen, Detlef Heck, Francesca-Fang Liao

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)990-1001
Number of pages12
JournalMolecular Psychiatry
Volume22
Issue number7
DOIs
StatePublished - Jul 1 2017

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Memory Disorders
Heat-Shock Response
Therapeutic Uses
Heat-Shock Proteins
Intraperitoneal Injections
Transcriptome
Neurodegenerative Diseases
Half-Life
Shock
Permeability
Alzheimer Disease
Central Nervous System
Hot Temperature
Pharmacology
Brain
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. / Wang, Bin; Liu, Yu; Huang, L.; Chen, J.; Li, J. J.; Wang, R.; Kim, E.; Chen, Y.; Justicia, C.; Sakata, Kazuko; Chen, Hao; Planas, A.; Ostrom, R. S.; Li, W.; Yang, G.; Mcdonald, Michael; Chen, R.; Heck, Detlef; Liao, Francesca-Fang.

In: Molecular Psychiatry, Vol. 22, No. 7, 01.07.2017, p. 990-1001.

Research output: Contribution to journalArticle

Wang, Bin ; Liu, Yu ; Huang, L. ; Chen, J. ; Li, J. J. ; Wang, R. ; Kim, E. ; Chen, Y. ; Justicia, C. ; Sakata, Kazuko ; Chen, Hao ; Planas, A. ; Ostrom, R. S. ; Li, W. ; Yang, G. ; Mcdonald, Michael ; Chen, R. ; Heck, Detlef ; Liao, Francesca-Fang. / A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. In: Molecular Psychiatry. 2017 ; Vol. 22, No. 7. pp. 990-1001.
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