Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Tauopathies, including Alzheimer's disease (AD), are characterized by pathological tau protein aggregation.
• Misfolded tau aggregates spread through the brain in a prion-like manner, contributing to neurodegeneration.
• Current therapeutic discovery models often use mutant tau or recombinant seeds, which do not fully replicate AD tau conformations.

Purpose of the Study:

• To establish a robust screening pipeline for discovering tau aggregation inhibitors.
• To integrate models using wildtype tau and disease-relevant seeds with established mutant tau models.
• To enhance the physiological relevance and translational potential of tauopathy drug discovery.

Main Methods:

• Developed a screening pipeline using HEK cells with wildtype tau seeded by Alzheimer's disease (AD) post-mortem tissue-derived aggregates.
• Employed primary mouse neurons expressing mutant tau seeded with recombinant aggregates as a complementary validation model.
• Initiated development of an induced pluripotent stem cell (iPSC)-derived neuronal model for seeded wildtype tau aggregation.

Main Results:

• Successfully identified inhibitors of tau aggregation using the developed pipeline.
• Demonstrated inhibitor efficacy in blocking AD-derived tau seeding in HEK cells.
• Validated inhibitor efficacy in preventing recombinant tau aggregation in primary neurons, showing broad applicability.

Conclusions:

• Established a robust pipeline for tau aggregation inhibitor discovery, bridging wildtype tau relevance and mutant tau models.
• The pipeline's physiological fidelity will be further enhanced by the iPSC-neuronal model.
• Compounds identified are progressing to mechanism of action studies, lead optimization, and preclinical evaluation for Alzheimer's disease and tauopathies.