Drug Development

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Synaptic degeneration, particularly of dendritic spines, is a hallmark of Alzheimer's disease (AD) and correlates with cognitive decline.
• p21-activated kinase 1 (PAK1) is a key regulator of cofilin and actin dynamics, crucial for synaptic spine integrity.
• PAK1 dysregulation, including translocation to the cell membrane, is observed in AD and linked to cognitive impairment.

Purpose of the Study:

• To investigate the therapeutic potential of inhibiting PAK1 to prevent synaptic spine loss in Alzheimer's disease.
• To test the hypothesis that PAK1 inhibition can confer resilience to dendritic spines against amyloid-beta (Aβ) and tau oligomers.

Main Methods:

• In vitro studies exposed mouse hippocampal neurons to Aβ or tau oligomers with or without the selective PAK1 inhibitor NVS-PAK1-1.
• In vivo studies involved oral administration of NVS-PAK1-1 to CD-1 and 5XFAD mice for pharmacokinetic-pharmacodynamic (PK-PD) analysis and dendritic spine quantitation.
• PAK1 activity was measured via western blotting for phosphorylated PAK1 (pPAK1).

Main Results:

• NVS-PAK1-1 demonstrated significant protection of dendritic spines against Aβ and tau oligomers in vitro (EC50 = 1 nM).
• Oral administration of NVS-PAK1-1 in 5XFAD mice achieved therapeutic brain concentrations and dose-dependently inhibited PAK1 activity.
• Treatment with NVS-PAK1-1 preserved dendritic spine density in 5XFAD mice to levels comparable to wild-type controls, without affecting amyloid levels.

Conclusions:

• Inhibition of PAK1 provides resilience to dendritic spines against Aβ and tau pathology in early-stage AD models.
• These findings support the investigation of PAK1 inhibitors as a potential therapeutic strategy for Alzheimer's disease.
• Existing clinical trials for PAK1 inhibitors in oncology may facilitate their translation to AD treatment.