Proinflammatory cytokines promote tau aggregation by inducing cleavage in human Alzheimer’s disease

Neuroinflammation and tau aggregation are hallmarks of Alzheimer’s disease (AD), yet the mechanistic link between them remains unknown. Analyzing a cohort of 46 AD and 40 control subjects using mass spectrometry-based proteomics, we identified a strong correlation between upregulation of the cytokine-induced antigen-presentation pathway and site-specific tau cleavage. This cleavage enriches the microtubule-binding repeat (MTBR) domain in AD tau aggregates; furthermore, synthetic MTBR fragments recapitulate tau aggregation both in vitro and in vivo. Our data show that the immunoproteasome (IP) colocalizes with tau aggregates in human AD neurons and drives the observed cleavage pattern. Proinflammatory cytokines reproduced AD-like tau cleavage and puncta formation in HEK293T cells expressing 0N4R tau, the hTau knock-in mouse, and human iPSC-derived neurons (iNeurons). IP knockdown via siRNA reduced tau-positive inclusion and upstream JAK/STAT pathway inhibition across model systems, including iNeurons, effectively abrogated cleavage and tau aggregation. These findings identify an inflammation-responsive pathway that promotes tau pathology and provide a mechanistic framework and potential therapeutic entry point for AD and potentially other tauopathies.