Rho-kinase ROCK inhibitors reduce oligomeric tau protein

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Neurofibrillary tangles, composed of hyperphosphorylated tau, are key pathological markers in Alzheimer's disease.
• Tau protein's affinity for microtubules decreases upon abnormal phosphorylation, leading to aggregation and tangle formation.
• Previous research indicated pitavastatin reduces tau via Rho-associated coiled-coil protein kinase (ROCK) inhibition.

Purpose of the Study:

• To investigate the detailed effects of Rho-associated coiled-coil protein kinase (ROCK) inhibitors on tau protein phosphorylation.
• To evaluate ROCK inhibitors as a potential therapeutic strategy for reducing pathogenic tau in tauopathies, including Alzheimer's disease.

Main Methods:

• Utilized a human neuroblastoma cell line (M1C cells) expressing wild-type tau protein.
• Employed primary cultured mouse neurons and a mouse model of tauopathy (rTG4510 line).
• Administered ROCK inhibitors (H1152, Y-27632, and fasudil) to assess their impact on tau pathology.

Main Results:

• ROCK inhibitors significantly reduced levels of phosphorylated tau and caspase-cleaved tau.
• Oligomeric tau levels were decreased, alongside inactivation of key tau kinases (GSK-3β, CDK5) and caspase.
• ROCK inhibitors activated protein phosphatase 2A, reduced IFN-γ levels, and enhanced autophagy and proteasome degradation pathways.

Conclusions:

• ROCK inhibitors effectively reduce pathogenic tau protein species, including phosphorylated and oligomeric forms.
• The mechanism involves modulation of tau kinases and phosphatases, and enhancement of cellular degradation systems.
• ROCK inhibitors show promise as a viable therapeutic approach for tauopathies like Alzheimer's disease.