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Abstract. Aggregation of amyloid-␤ (A␤) and tau plays a crucial role in the onset and progression of Alzheimer's disease (AD). Therefore, the inhibition of A␤ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both A␤ and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on A␤ aggregation in vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of A␤ and tau aggregation in vivo. PE859 inhibited A␤ aggregation in vitro and protected cultured cells from A␤-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated A␤ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.

In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies.