Tau strains shape disease.

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Tauopathies encompass over 25 neurodegenerative diseases, including AGD, PSP, CBD, and PiD.
• These diseases are defined by the brain accumulation of abnormal tau protein aggregates, strongly linked to dementia.
• Mutations in tau can increase its aggregation, contributing to disease pathogenesis.

Purpose of the Study:

• To investigate the prion-like behavior of tau protein in neurodegenerative diseases.
• To explore the relationship between tau conformation, strain propagation, and distinct neuropathological patterns.
• To establish causality between tau structure and disease in human tauopathies.

Main Methods:

• Analysis of tau fibril structures using cryo-electron microscopy (Cryo-EM) from patient brains.
• Propagation of tau strains in cultured cells.
• Inoculation of tau strains into mouse models to observe neuropathological outcomes.
• Examination of tau monomer conformations within different fibril subtypes.

Main Results:

• Tau protein propagates unique strains in cell cultures and mouse models, creating defined neuropathological patterns.
• Distinct tau fibril structures (cores) are observed across different tauopathies.
• The conformation of tau monomers within fibrils appears preserved, suggesting specific templating roles.
• Local motifs in tau monomers influence their propensity to adopt distinct conformations.

Conclusions:

• The prion hypothesis provides a framework for understanding the diversity of human tauopathies.
• Tau protein exhibits prion-like properties, where specific conformations dictate disease characteristics.
• Accurate classification of patients based on tau aggregate structure is crucial for diagnosis and targeted therapies.