Barbatolic Acid Prevents Tau and Amylin Interaction and Stimulates the Growth of Acetylated Microtubules in Cell Culture.

INTRODUCTION

Neurodegenerative disorders, including Alzheimer's disease and related tauopathies, involve tau aggregates that correlate closely with cognitive decline. Clinical evidence indicates that patients with type 2 diabetes-characterized by amylin accumulation-experience exacerbated neurodegenerative symptoms, suggesting a cooperative pathologic effect between both proteins.

METHODS

Using isothermal titration calorimetry, fluorimetry, intrinsic fluorescence, molecular docking, cell culture, and confocal microscopy, we characterized the hydrophobic interactions driving the tau-amylin relationship and evaluated the efficacy of small molecules to inhibit these interactions and protect microtubule stability.

RESULTS

Tau and amylin co-assemble into morphologically distinct amyloid structures driven by hydrophobic interactions. Notably, barbatolic acid and divaricatic acid effectively disrupt this interprotein interaction. In Neuro2a (N2a) cell cultures, barbatolic acid promoted neuronal differentiation more effectively than retinoic acid. Furthermore, N2a cells exposed to tau aggregates pre-treated with barbatolic acid maintained intact acetylated microtubule networks, indicating a protective role in preserving cytoskeletal stability.

DISCUSSION: The tau-amylin interaction can be disrupted by barbatolic and divaricatic acid via interference with key lysine residues, offering a plausible therapeutic strategy to mitigate aggregate toxicity. Additionally, the unique ability of barbatolic acid to preserve and promote stable microtubule formation reveals a novel dual mechanism of action.

CONCLUSION

Because current treatments for neurodegenerative diseases remain palliative, developing multi-target compounds with these dual characteristics offers a promising path forward in pharmacophore design.