TARGETING TAU AGGREGATION AND PHOSPHORYLATION WITH DDMC, A NON-ANTIBIOTIC TETRACYCLINE

Tau aggregation and conformational dysregulation are central features of some neurodegenerative disorders and contribute to cytoskeletal collapse and neuronal dysfunction. Building on our previous evidence showing that DDMC, a non-antibiotic tetracycline, exerts neuroprotective effects in Parkinson’s disease models and modulates α-synuclein aggregation, we aimed to evaluate whether DDMC can also target Tau-driven pathogenic mechanisms, supporting a shared therapeutic strategy for proteinopathy co-pathologies. Recombinant human Tau aggregation was induced in vitro and monitored using Thioflavin T fluorescence assays, including real-time quaking-induced conversion (RT-QuIC) assays and complemented by transmission electron microscopy and hydrophobic surface exposure assessments. In parallel, DDMC effects were tested in SH-SY5Y and U2OS cellular models of Tau hyperphosphorylation, with microtubule organization as a functional readout. DDMC significantly modifies Tau aggregation kinetics and assembly features, generating conformationally distinct species with reduced hydrophobic exposure compared to untreated aggregates. Importantly, in both cellular models, DDMC restored microtubule bundling in a concentration-dependent manner, reversing the diffuse cytoskeletal phenotype associated with hyperphosphorylated Tau. Moreover, molecular modelling predicted specific interactions between DDMC and the Tau VQIVYK aggregation motif, suggesting a mechanism linking modulation of Tau assembly with preservation of microtubule-associated function. Collectively, these findings identify DDMC as a modulator of Tau pathology, capable of preserving cytoskeletal organization and highlighting a promising therapeutic avenue targeting convergent mechanisms across neurodegenerative proteinopathies.