title: A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism.
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.
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: B
authors.identifier: 0000-0001-9032-5009
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Anatomy &Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, New York University School of Medicine, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: J J
authors.identifier: 0000-0002-2730-9361
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Brain Ischemia and Neurodegeneration, Institute for Biomedical Research (IIBB-CSIC), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Justicia
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Sakata
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Brain Ischemia and Neurodegeneration, Institute for Biomedical Research (IIBB-CSIC), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Planas
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Ostrom
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, New York University School of Medicine, New York, NY, USA.
authors.forename: G
authors.identifier: 0000-0002-5739-9126
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Anatomy &Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.|Department of Neurology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: McDonald
authors.affiliation: Oncosynergy, Inc San Francisco, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Anatomy &Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Heck
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
authors.forename: F-F
authors.initials: FF
authors.lastname: Liao
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D014157:Transcription Factors