Linking HSP90 target occupancy to HSP70 induction and efficacy in mouse brain

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Heat shock protein 90 (HSP90) is a molecular chaperone implicated in neurodegenerative diseases like Alzheimer's.
• HSP90 inhibition is a potential therapeutic strategy to clear pathological proteins, but the exact mechanisms are unclear.
• Potential mechanisms include direct ATPase inhibition or indirect induction of other chaperones like HSP70.

Purpose of the Study:

• To develop methods for studying HSP90 target occupancy and HSP70 induction in vivo.
• To investigate the effects of HSP90 inhibitors on synaptic dysfunction in a mouse model of Alzheimer's disease.
• To explore the therapeutic relevance of HSP90 inhibition for neurodegenerative disorders.

Main Methods:

• Established in vivo methodologies to measure HSP90 target engagement and HSP70 induction.
• Administered two distinct HSP90 inhibitors to the rTg4510 transgenic mouse model of Alzheimer's disease.
• Assessed the impact of inhibitors on tau-mediated synaptic dysfunction.

Main Results:

• Demonstrated a correlation between HSP90 inhibition and HSP70 induction in vivo.
• Showed that a specific HSP90 inhibitor reversed synaptic impairments in the Alzheimer's disease mouse model.
• Identified a compound with high HSP70 induction capacity as effective in reversing synaptic deficits.

Conclusions:

• Developed novel assay methodologies for elucidating HSP90 inhibition mechanisms in neurodegeneration.
• HSP90 inhibitors can normalize synaptic dysfunction in an in vivo Alzheimer's disease model.
• These findings support the therapeutic potential of HSP90 inhibition and validate the rTg4510 model for pharmacodynamic studies.