Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease

Jong Hyun Park, Yeon Ha Ju, Ji Won Choi, Hyo Jung Song, Bo Ko Jang, Junsung Woo, Heejung Chun, Hyeon Jeong Kim, Su Jeong Shin, Oleg Yarishkin, Seonmi Jo, Mijeong Park, Seul Ki Yeon, Siwon Kim, Jeongyeon Kim, Min Ho Nam, Ashwini M. Londhe, Jina Kim, Sung Jin Cho, Suengmok ChoChangho Lee, Sung Yeoun Hwang, Sang Wook Kim, Soo Jin Oh, Jeiwon Cho, Ae Nim Pae, C. Justin Lee, Ki Duk Park

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer’s disease (AD) because of its association with aberrant -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 (IC 50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term 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.

Original languageEnglish
Article numbereaav0316
JournalScience Advances
Volume5
Issue number3
DOIs
StatePublished - 2019

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