Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Cellular Biology
• Pharmacology

Background:

• Microtubule-associated protein tau's role shifts from neuroprotection to disease pathogenesis under stress.
• Cellular senescence, termed 'neurescence' in neurons, stabilizes stressed cells but impairs the brain microenvironment.
• Tau-induced neurescence highlights a dual role in neuronal stability and disease progression.

Purpose of the Study:

• Investigate tau protein heterogeneity and identify neurescent cells using spatial proteogenomics.
• Predict therapeutic targets for tauopathies.
• Evaluate senolytics (dasatinib and quercetin [D+Q], fisetin) in preclinical models and Phase I clinical trials for Alzheimer's disease.

Main Methods:

• Applied spatial proteogenomics to human postmortem brain tissue.
• Conducted preclinical studies with senolytic interventions in tauopathy mouse models.
• Performed Phase I clinical testing of D+Q in Alzheimer's disease patients to assess safety and biomarkers.

Main Results:

• Spatial proteogenomics revealed tau heterogeneity and identified neurescent cells and therapeutic targets.
• Senolytic treatment with D+Q outperformed fisetin in reducing pathogenic tau in preclinical models.
• Spatial proteogenomics provided insights into senolytic target engagement across brain cell types and regions, aiding interpretation of clinical biomarker data.

Conclusions:

• Tau-induced neurescence demonstrates tau's dual neuroprotective and pathogenic roles.
• Targeting tau-induced senescence with senolytics is a promising strategy for mitigating tau-driven neurodegeneration.
• The D+Q combination therapy is under investigation in a Phase 2 clinical trial (NCT04685590) for Alzheimer's disease.