Journal
SCIENCE ADVANCES
Volume 5, Issue 3, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aav0316
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Funding
- National Research Council of Science & Technology (NST) - Korean government (MSIP) [CRC-15-04-KIST]
- Drug Development Project of Korea Drug Development Fund [KDDF-2105-09-06]
- National Research Foundation of Korea [NRF-2018M3A9C8016849]
- Main Research Program of the Korea Food Research Institute (KFRI) [E0164503-01]
- Creative Research Initiative Program
- Korean National Research Foundation [2015R1A3A2066619]
- KIST Institutional Grant [2E26662]
- KU-KIST Graduate School of Science and Technology program [R1435281]
- National Research Foundation of Korea [2015R1A3A2066619] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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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