Disease-specific tau polymorphs are associated with unique protein networks across proteinopathies.

Distinct tau polymorphs in Alzheimer’s disease, PSP, and DLB associate with unique protein interaction networks, with 493 high-confidence interactors identified.

• Why it matters: Understanding disease-specific tau interactions is crucial because tau aggregates adopt different conformations across tauopathies, yet their protein networks remain poorly characterized, limiting insights into disease mechanisms.
• What they did: The study used interactome profiling of tau aggregates from brain fractions and applied machine learning with four to six protein features to distinguish diseases, identifying disease-specific interactors and post-translational modifications.
• The result: Findings reveal that tau polymorph conformations are linked to distinct interaction networks, such as glycolytic enzymes in AD and neurogenesis modulators in DLB, advancing molecular understanding of tauopathy heterogeneity.