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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 neurons, Presenilin 1(PS1)/γ‐secretase is located at the synapses, bound to N‐cadherin. We have previously reported that N‐cadherin‐mediated cell–cell contact promotes cell‐surface expression of PS1/γ‐secretase. We postulated that N‐cadherin‐mediated trafficking of PS1 might impact synaptic PS1‐amyloid precursor protein interactions and Aβ generation. In the present report, we evaluate the effect of N‐cadherin‐based contacts on Aβ production. We demonstrate that stable expression of N‐cadherin in Chinese hamster ovary cells, expressing the Swedish mutant of human amyloid precursor protein leads to enhanced secretion of Aβ in the medium. Moreover, N‐cadherin expression decreased Aβ42/40 ratio. The effect of N‐cadherin expression on Aβ production was accompanied by the enhanced accessibility of PS1/γ‐secretase to amyloid precursor protein as well as a conformational change of PS1, as demonstrated by the fluorescence lifetime imaging technique. These results indicate that N‐cadherin‐mediated synaptic adhesion may modulate Aβ secretion as well as the Aβ42/40 ratio via PS1/N‐cadherin interactions.