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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 | 2017

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.

Pubmed ID: 27457810 RIS Download

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Associated grants

  • Agency: NIMH NIH HHS, United States
    Id: R03 MH102445
  • Agency: NIMH NIH HHS, United States
    Id: R21 MH105567
  • Agency: NIA NIH HHS, United States
    Id: R21 AG041935
  • Agency: NIA NIH HHS, United States
    Id: R01 AG049772
  • Agency: NCI NIH HHS, United States
    Id: R01 CA148706
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM107469
  • Agency: NIA NIH HHS, United States
    Id: R21 AG048410
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM107094
  • Agency: NINDS NIH HHS, United States
    Id: R21 NS091752
  • Agency: NIA NIH HHS, United States
    Id: R01 AG040230

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