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A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse
1Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
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.
Insights
Pharmacological heat-shock protein 90 (Hsp90) inhibitors show promise for neurodegenerative diseases. A novel Hsp90 inhibitor, OS47720, demonstrated synaptic protection in Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Heat-shock protein 90 (Hsp90) inhibitors are explored for neuroprotection in neurodegenerative diseases.
- Systemic toxicity and poor brain penetration limit current Hsp90 inhibitor therapies.
- Alzheimer's disease models present challenges for effective drug delivery and safety.
Purpose of the Study:
- To evaluate the efficacy and safety of a novel Hsp90 inhibitor, OS47720, in a mouse model of Alzheimer's disease.
- To investigate the mechanism of action of OS47720, focusing on heat-shock factor 1 (HSF1) activation and its downstream effects.
- To determine if OS47720 can provide synaptic protection without systemic toxicity.
Main Methods:
- Chronic administration of OS47720 to symptomatic Tg2576 mice (an Alzheimer's disease model).
- Assessment of heat-shock-like response and synaptic protection.
- Pharmacokinetic analysis of OS47720 in mouse brain and measurement of HSF1 activation.
- Analysis of HSF1-mediated transcriptional changes in synaptic genes.
Main Results:
- OS47720 treatment induced a heat-shock-like response and provided synaptic protection in Alzheimer's disease model mice.
- No significant systemic toxicity was observed despite the drug's short brain half-life.
- A single OS47720 injection led to rapid and sustained (>3 days) nuclear HSF1 activation.
- The protective effects were dependent on HSF1 activation and subsequent modulation of synaptic gene transcription.
Conclusions:
- OS47720 is a promising Hsp90 inhibitor for Alzheimer's disease, offering synaptic protection with reduced systemic toxicity.
- HSF1 activation is a key mechanism underlying the therapeutic benefits of OS47720.
- This study highlights a novel role for HSF1 in synaptic function and memory, potentially via synaptic transcriptome regulation.
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