Abstract
In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.
Original language | English |
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Pages (from-to) | 886-896 |
Number of pages | 11 |
Journal | Nature Medicine |
Volume | 20 |
Issue number | 8 |
DOIs | |
Publication status | Published - Aug 2014 |
Bibliographical note
Funding Information:This work was supported by the WCI Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP: to C.J.L., NRF grant number: WCI 2009-003), the KIST Institutional Flagship Program (to C.J.L., 3E25022; to H.R., 2E24380), the National Leading Research Laboratory Program of Korea and the KAIST Future Systems Healthcare Project (to D.K., NRF grant number: 2011-0028772), the Basic Science Research Program through the NRF funded by the MSIP (to Y.C.B., 2008-0062282), and the National Institute of Aging of USA (to N.W.K.). We thank Mazence for APP/PS1 mice, W. Park (GIST) for 5XFAD mice, K. Park and H. Song (KIST) for safinamide and K. Fujiwara (Sojo University) for the putrescine-specific antibody.