Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease
- 주제(기타) Multidisciplinary Sciences
- 설명문(일반) [Park, Jong-Hyun; Choi, Ji Won; Song, Hyo Jung; Jang, Bo Ko; Kim, Hyeon Jeong; Shin, Su Jeong; Yeon, Seul Ki; Kim, Siwon; Londhe, Ashwini M.; Oh, Soo-Jin; Pae, Ae Nim; Park, Ki Duk] Korea Inst Sci & Technol, Convergence Res Ctr Diag Treatment & Care Syst De, Seoul 02792, South Korea; [Ju, Yeon Ha; Woo, Junsung; Yarishkin, Oleg; Jo, Seonmi; Kim, Jeongyeon; Nam, Min-Ho; Lee, C. Justin] Korea Inst Sci & Technol, Ctr Neurosci & Funct Connect, Brain Sci Inst, Seoul 02792, South Korea; [Ju, Yeon Ha; Kim, Siwon; Londhe, Ashwini M.; Pae, Ae Nim; Lee, C. Justin; Park, Ki Duk] Korea Univ Sci & Technol, KIST Sch, Div Biomed Sci & Technol, Seoul 02792, South Korea; [Ju, Yeon Ha; Woo, Junsung; Chun, Heejung; Nam, Min-Ho; Oh, Soo-Jin; Lee, C. Justin] Korea Inst Sci & Technol, Ctr Glia Neuron Interact, Seoul 02792, South Korea; [Kim, Hyeon Jeong; Shin, Su Jeong; Yeon, Seul Ki] Yonsei Univ, Dept Biotechnol, Seoul 03722, South Korea; [Park, Mijeong; Cho, Jeiwon] Catholic Kwandong Univ, Coll Med, Dept Med Sci, Incheon 22711, South Korea; [Kim, Jina; Cho, Sung Jin] Daegu Gyeongbuk Med Innovat Fdn, New Drug Dev Ctr, Daegu 41061, South Korea; [Cho, Suengmok; Lee, Changho] Pukyong Natl Univ, Dept Food Sci & Technol, Busan 48513, South Korea; [Hwang, Sung Yeoun; Kim, Sang Wook] KEMIMEDI, 5F Hanil Bldg,Nonhyeon Ro 652, Seoul 06106, South Korea; [Hwang, Sung Yeoun; Kim, Sang Wook] MEGABIOWOOD, 5F Hanil Bldg,Nonhyeon Ro 652, Seoul 06106, South Korea; [Lee, C. Justin] Inst for Basic Sci Korea, Ctr Cognit & Social, Daejeon 34126, South Korea; [Park, Ki Duk] Kyung Hee Univ, KHU KIST Dept Converging Sci & Technol, Seoul 02447, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 AMER ASSOC ADVANCEMENT SCIENCE
- 발행년도 2019
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000171983
- 본문언어 영어
- Published As https://dx.doi.org/10.1126/sciadv.aav0316
초록/요약
Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant gamma-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Longterm treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.
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