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Abstract
Rhizolutin (1) was discovered as a natural product of ginseng-rhizospheric Streptomyces sp. WON17. Its structure features an unprecedented 7/10/6-tricyclic dilactone carbon skeleton composed of dimethylcyclodecatriene flanked by a 7-membered and a 6-membered lactone ring based on spectroscopic analysis. During an unbiased screening of natural product libraries, this novel compound was found to dissociate amyloid-β (Aβ) plaques and tau tangles, which are key pathological hallmarks of Alzheimer's disease (AD). Rhizolutin treatment of APP/PS1 double transgenic mice with AD significantly dissociated hippocampal plaques. In vitro, rhizolutin substantially decreased Aβ-induced apoptosis and inflammation in neuronal and glial cells. Our findings introduce a unique chemical entity that targets Aβ and tau concurrently by mimicking misfolded protein clearance mechanisms of immunotherapy, which is prominently investigated in clinical trials.

Affiliations

Yun Kwon  1 , Jisu Shin  2 , Kwangho Nam  3 , Joon Soo An  1 , Seung-Hoon Yang  4 , Seong-Heon Hong  1 , Munhyung Bae  1 , Kyuho Moon  1 , Yakdol Cho  5 , Jiwan Woo  5 , Keunwan Park  6 , Kyeonghwan Kim  2 , Jongheon Shin  1 , Byung-Yong Kim  7 , YoungSoo Kim  2 , Dong-Chan Oh  1
1 Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
2 Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
3 Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, 76019, USA.
4 Department of Medical Biotechnology, Dongguk University, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Republic of Korea.
5 Research Animal Resource Center, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
6 Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), 679 Saimdang-ro, Gangneung-si, Gangwon-do, 25451, Republic of Korea.
7 Microbiome Research Centre, ChunLab, Inc., 2477, JW Tower 6F, Nambusunhwan-ro, Seocho-gu, Seoul, 06725, Republic of Korea.