To target Tau pathologies, we must embrace and reconstruct their complexities

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Tau aggregation is a hallmark of Tauopathies, including Alzheimer's disease.
• Heparin has been used to induce Tau aggregation in vitro, aiding research.
• However, heparin-induced Tau fibrils lack the properties of disease-associated fibrils.

Purpose of the Study:

• To review the evolution of Tau-heparin interactions and aggregation models.
• To compare in vitro heparin-induced Tau fibrils with brain-derived fibrils.
• To explore determinants of Tau pathological heterogeneity and identify knowledge gaps.

Main Methods:

• Literature review and analysis of existing studies on Tau aggregation.
• Comparative analysis of biochemical and ultrastructural properties of Tau fibrils.
• Synthesis of current understanding and identification of future research directions.

Main Results:

• Heparin-induced Tau fibrils do not accurately mimic disease-associated Tau fibrils.
• Significant differences exist in biochemical and ultrastructural properties.
• Current in vitro models require reassessment for better disease relevance.

Conclusions:

• Reassess current approaches for studying Tau aggregation in vitro.
• Investigate naturally occurring cofactors involved in Tau pathology initiation and spread.
• Develop improved in vitro methods to recapitulate pathological Tau complexity for better drug development.