HSP90 is involved in curcumin-mediated inhibition of tau aggregation

Tau aggregation in neurons is a pathological hallmark of Alzheimer's disease (AD). The development of therapeutic drugs that inhibit tau aggregation in tauopathies, including AD, remains challenging. Herein, we developed a tau self-interaction reporter system using split Nanoluciferase (Tau-NLuc) in which luciferase activity is restored by the self-assembly of split Nanoluciferases following self-interaction between tau proteins. Curcumin (CCM), a phenolic organic compound, significantly reduced luciferase activity in the Tau-NLuc system, including mutant tau forms such as S396/404E and P301L, which are known aggregation-prone tau forms, suggesting that CCM may act as a potential inhibitor of tau aggregation. CCM did not alter the protein levels of phosphorylated tau as well as total tau, indicating that the reduction in luciferase activity by CCM did not originate from tau degradation, but rather from tau aggregation inhibition. Of note, CCM significantly increased heat shock protein (HSP) 90 dimer. The reduced luciferase activity in the Tau-NLuc system by CCM was recovered by knockdown of the HSP90 gene using a siRNA specific for HSP90 or treatment of an inhibitor of HSP90 NCT-58, supporting the involvement of HSP90. Intriguingly, hexahydrocurcumin (HHC), a derivative of CCM, did not reduce luciferase activity, nor did it induce the formation of the HSP90 dimer, suggesting that HSP90 dimer formation may contribute to the CCM-mediated inhibition of tau aggregation. Taken together, the results demonstrate that CCM inhibits tau aggregation with the involvement of HSP90, providing novel insights into the development of therapeutic strategies for AD.