Disease-specific tau polymorphs define unique protein interaction networks across proteinopathies.

Tau protein aggregates exhibit distinct conformations across tauopathies, but their disease-specific protein interactions remain poorly understood. Here, we demonstrate that disease-specific tau conformations determine unique protein interaction landscapes across Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Through comprehensive interactome profiling of misfolded tau aggregates from PBS- and sarkosyl-soluble fractions. We identified 493 high-confidence proteins with remarkable disease specificity-notably, no common interactors overlapping across all three tauopathies. Machine learning classification achieved compelling discrimination between diseases using as few as 4-6 proteins features, demonstrating robust molecular signatures underlying clinical heterogeneity. AD derived tau aggregates uniquely engaged cellular metabolism machinery, including key glycolytic enzymes and TCA cycle proteins, alongside glutamate/GABA neurotransmitter cycling components, with the astrocytic glutamate transporter SLC1A2 showing 27-fold enrichment over other tauopathies. In contrast, PSP tau displayed the most distinctive profile, with extensive protein depletion (52/57 significant proteins) and selective enrichment of proteasome components, particularly PSMB7 showing >3000-fold abundance. DLB tau is associated with neurogenesis modulators while depleting neuroinflammatory mediators. These interaction patterns were validated through proximity ligation assays and correlated with distinct post-translational modification profiles, with PSP tau exhibiting globally elevated ubiquitination, AD showing mixed modification patterns, and DLB displaying minimal ubiquitination. Critically, sarkosyl-soluble fractions revealed reduced interactome complexity across diseases, except for PSP tau which maintained robust interactions with GPCR-ERK signaling and kinetochore proteins, suggesting unique aggregation mechanisms. Our findings establish that conformationally distinct tau strains dictate disease-specific protein interaction networks, providing molecular insight into tauopathy diversity and identifying novel therapeutic targets for precision medicine approaches in neurodegeneration.