PE859, A Novel Curcumin Derivative, Inhibits Amyloid-β and Tau Aggregation, and Ameliorates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8

Article type: Research Article

Authors: Okuda, Michiaki^{a; b; c; *} | Fujita, Yuki^{a; c} | Hijikuro, Ichiro^d | Wada, Mei^e | Uemura, Takuya^e | Kobayashi, Yukako^e | Waku, Tomonori^e | Tanaka, Naoki^e | Nishimoto, Takaaki^f | Izumi, Yasuhiko^b | Kume, Toshiaki^b | Akaike, Akinori^{b; g} | Takahashi, Takashi^h | Sugimoto, Hachiro^a

Affiliations: [a] Graduate School of Brain Science, Doshisha University, Kizugawa, Kyoto, Japan | [b] Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan | [c] Pharma Eight Co., Ltd., Kyoto, Japan | [d] Farnex Inc., Tokyo, Japan | [e] Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Kyoto, Japan | [f] Department of Immunology, Kawasaki Medical School, Kurashiki, Japan | [g] Laboratory of Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan | [h] Natural Product Chemistry & Pharmaceutical Research Center, Yokohama College of Pharmacy, Yokohama, Japan

Correspondence: [*] Correspondence to: Michiaki Okuda, Graduate School of Brain Science, Doshisha University, 4-1-1 Kizugawadai, Kizugawa, Kyoto, 619-0225, Japan. Tel./Fax: +81 774 65 7498; E-mail: [email protected].

Abstract: Aggregation of amyloid-β (Aβ) and tau plays a crucial role in the onset and progression of Alzheimer’s disease (AD). Therefore, the inhibition of Aβ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aβ 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 Aβ aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aβ and tau aggregation in vivo. PE859 inhibited Aβ aggregation in vitro and protected cultured cells from Aβ-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aβ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.

Keywords: Aggregation inhibitor, Alzheimer’s disease, amyloid-β , tau

DOI: 10.3233/JAD-161017

Journal: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 313-328, 2017