GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease
Open accessAbstract
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.
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Astroglial reactivity impacts astrocyte-dependent glutamate homeostasis.
“As astroglial reactivity impacts astrocyte‐dependent glutamate homeostasis [36, 94, 95, 96, 97]”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [97]
The Results (Reactive astrocytes abnormally release GABA; page unavailable) show that the glutamate-releasing Best1 channel is reduced in the synaptic microdomains of reactive astrocytes in AD-model mice. The Discussion describes its redistribution, but the paper does not establish an effect on glutamate homeostasis, such as altered glutamate uptake or extracellular levels. (LLM, conf=0.82)
Experimental — accuracy not yet measuredExcessive release of GABA by reactive astrocytes in AD and Parkinson's disease may be a case of gain of detrimental function.
“The excessive release of GABA by reactive astrocytes in AD63 and Parkinson’s disease64 may be a case of gain of detrimental function.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [63]
Hyperactivated astrocytes and microglia support excitotoxicity through the exacerbated release of glutamate in response to Aβ, and GABA‐producing astrocytes are commonly found in AD.
“hyperactivated astrocytes and microglia, support excitotoxicity through the exacerbated release of glutamate in response to Aβ [37, 38, 40, 43, 50, 51, 117, 118], and even GABA‐producing astrocytes are commonly found in AD [42, 97, 119].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [97]
Reactive astrocytes surrounding Aβ deposits show enhanced synthesis and release of GABA, which increases tonic inhibition of dentate granule cells and negatively impacts memory processing.
“Another signaling aberration seen in reactive astrocytes sur rounding Aβ deposits consists in an enhanced synthesis and release of the transmitter GABA 103-105 , which increases tonic inhibition of dentate granule cells with a negative impact on memory processing.”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [105]
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- Authors
- Jo, S., Yarishkin, O., Hwang, Y. J., Chun, Y. E., Park, M., Woo, D. H., Bae, J. Y., Kim, T., Lee, J., Chun, H., Park, H. J., Lee, D. Y., Hong, J., Kim, H. Y., Oh, S.-J., Park, S. J., Lee, H., Yoon, B.-E., Kim, Y., Jeong, Y., Shim, I., Bae, Y. C., Cho, J., Kowall, N. W., Ryu, H., Hwang, E., Kim, D., & Lee, C. J.
- Affiliations
- Korea Advanced Institute of Science and Technology (KR)
- Korea Institute of Science and Technology (KR)
- Kyungpook National University (KR)
- Kyung Hee University (KR)
- Boston University (US)
- Corresponding author
- Kim, Daesoo
- Lee, C Justin
- ORCID
- Jo, Seonmi
- Yarishkin, Oleg
- Park, Mijeong
- Woo, Dong Ho
- Bae, Jin Young
- Lee, Jaekwang
- Chun, Heejung
- Park, Hyun Jung
- Lee, Da Yong
- Hong, Jinpyo
- Kim, Hye Yun
- Oh, Soo-Jin
- Park, Seung Ju
- Lee, Hyo
- Yoon, Bo-Eun
- Kim, YoungSoo
- Jeong, Yong
- Shim, Insop
- Bae, Yong Chul
- Cho, Jeiwon
- Kowall, Neil W
- Ryu, Hoon
- Hwang, Eunmi
- Kim, Daesoo
- Lee, C Justin
- Venue
- Nature Medicine
- Published
- 2014-06-29
- Volume
- 20
- Issue
- 8
- Pages
- 886-896
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC8385452
- OpenAlex
- W2000225222
- Cited by
- 783
- References
- 71
- Citations by year
- 2026: 53 · 2025: 60 · 2024: 83 · 2023: 101 · 2022: 94 · 2021: 72 · 2020: 66 · 2019: 56 · 2018: 62 · 2017: 54 · 2016: 35 · 2015: 40 · 2014: 5
- FWCI
- 30.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30AG013846)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, reactive astrocytes, GABA, monoamine oxidase B, memory impairment, dentate gyrus, granule cells, synaptic plasticity, learning and memory, amyloid plaques, treatment options
- MeSH terms
- Bestrophins, Alzheimer Disease, Animals, Astrocytes, Cerebellum, Disease Models, Animal, Eye Proteins, gamma-Aminobutyric Acid, Hippocampus, Humans, Ion Channels, Male, Memory, Memory Disorders, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Transgenic, Monoamine Oxidase, Monoamine Oxidase Inhibitors, Peptide Fragments, Putrescine, Amyloid beta-Peptides, Receptors, GABA, GABA Antagonists, Maze Learning, Dentate Gyrus, RNA, Small Interfering, Mice, Amyloid Precursor Protein Secretases, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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