Park, Jong-Hyun Ju, Yeon Ha Choi, Ji Won Song, Hyo Jung Jang, Bo Ko Woo, Junsung Chun, Heejung Kim, Hyeon Jeong Shin, Su Jeong Yarishkin, Oleg Jo, Seonmi Park, Mijeong Yeon, Seul Ki Kim, Siwon Kim, Jeongyeon Nam, Min-Ho Londhe, Ashwini M. Kim, Jina Cho, Sung Jin Cho, Suengmok Lee, Changho Hwang, Sung Yeoun Kim, Sang Wook Oh, Soo-Jin Cho, Jeiwon Pae, Ae Nim Lee, C. Justin Park, Ki Duk 2024-01-19T20:33:51Z 2024-01-19T20:33:51Z 2021-09-02 2019-03 2375-2548 https://pubs.kist.re.kr/handle/201004/120316 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. English American Association for the Advancement of Science Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease Article 10.1126/sciadv.aav0316 1 Science Advances, v.5, no.3 Science Advances 5 3 N scie scopus 000462564300043 2-s2.0-85063344007 Multidisciplinary Sciences Science & Technology - Other Topics Article L-DEPRENYL CLINICAL-TRIALS GABA BRAIN SELEGILINE ASTROCYTES UPDATE