Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tau aggregation is a key feature of tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and Pick's disease (PiD).
• Biochemical variations in tau aggregates, such as isoform composition (3R, 4R, or 3R+4R) and post-translational modifications, may contribute to differing toxicities.
• Existing models often use tau overexpression or synthetic fibrils, lacking the biochemical complexity of disease-derived tau.

Purpose of the Study:

• To develop an over-expression-free tau seeding model using disease-derived tau aggregates.
• To enable broader investigations into tau interactions, cellular toxicity, and potential therapeutic interventions across various cell types.
• To provide a more physiologically relevant platform for studying tau pathology.

Main Methods:

• Purification and biochemical characterization (mass spectrometry) of tau aggregates from human brain tissue (AD, PiD, PSP, controls).
• Seeding of purified tau aggregates onto diverse cell lines (SH-SY5Y, M03.13, U-87, U-118) to induce aggregation.
• Quantification of tau aggregates via imaging and assessment of cytotoxicity and pathway disruptions (autophagy, lysosomes, mitochondria).

Main Results:

• Disease-derived tau seeds successfully induced titratable tau aggregation in multiple cell lines, retaining disease-specific properties.
• Mass spectrometry confirmed expected tau isoform biases (e.g., elevated 4R tau in AD/PSP) and identified APP enrichment in AD preparations.
• Pick's disease (PiD)-derived tau seeds demonstrated the highest seeding capacity, and tau seeds induced distinct pathway-specific disruptions, including increased p62 puncta formation.

Conclusions:

• The developed tau seeding model offers a robust and disease-specific platform for studying tau pathology.
• This over-expression-free approach provides a more physiologically relevant model for investigating tau interactions.
• The model facilitates the assessment of therapeutic strategies targeting tau aggregation and toxicity in a disease context.