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 language | English |
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Article number | eaav0316 |
Journal | Science Advances |
Volume | 5 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2019 |
Bibliographical note
Funding Information:We thank H. Hwang for in vitro ADME/Tox tests. We also acknowledge a number of colleagues for critical feedback on the manuscript. This work was supported by the National Research Council of Science & Technology (NST) grant by the Korean government (MSIP) (no. CRC-15-04-KIST to K.D.P.), the Drug Development Project (KDDF-2105-09-06 to K.D.P.) of Korea Drug Development Fund, the National Research Foundation of Korea (NRF-2018M3A9C8016849 to K.D.P.), the Main Research Program (E0164503-01 to K.D.P.) of the Korea Food Research Institute (KFRI), the Creative Research Initiative Program, the Korean National Research Foundation (2015R1A3A2066619 to C.J.L.), the KIST Institutional Grant (2E26662 to C.J.L.), and the KU-KIST Graduate School of Science and Technology program (R1435281 to C.J.L.).
Publisher Copyright:
Copyright © 2019 The Authors, some rights reserved.
All Science Journal Classification (ASJC) codes
- General