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.
Similar content being viewed by others
References
Alzheimer's Association. 2012 Alzheimer's disease facts and figures. Alzheimers Dement. 8, 131–168 (2012).
Mattson, M.P. Pathways towards and away from Alzheimer's disease. Nature 430, 631–639 (2004).
Mucke, L. & Selkoe, D.J. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb. Perspect. Med. 2, a006338 (2012).
Ballatore, C., Lee, V.M.-Y. & Trojanowski, J.Q. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat. Rev. Neurosci. 8, 663–672 (2007).
Eddleston, M. & Mucke, L. Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54, 15–36 (1993).
Wisniewski, H.M. & Wegiel, J. Spatial relationships between astrocytes and classical plaque components. Neurobiol. Aging 12, 593–600 (1991).
Sofroniew, M.V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647 (2009).
Kuchibhotla, K.V., Lattarulo, C.R., Hyman, B.T. & Bacskai, B.J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).
Woo, D.H. et al. TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell 151, 25–40 (2012).
Henneberger, C., Papouin, T., Oliet, S.H. & Rusakov, D.A. Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010).
Blum, A.E., Joseph, S.M., Przybylski, R.J. & Dubyak, G.R. Rho-family GTPases modulate Ca2+-dependent ATP release from astrocytes. Am. J. Physiol. Cell Physiol. 295, C231–C241 (2008).
Lee, S. et al. Channel-mediated tonic GABA release from glia. Science 330, 790–796 (2010).
Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat. Rev. Neurosci. 6, 215–229 (2005).
Samakashvili, S. et al. Analysis of chiral amino acids in cerebrospinal fluid samples linked to different stages of Alzheimer disease. Electrophoresis 32, 2757–2764 (2011).
Yoshiike, Y. et al. GABAA Receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin. PLoS ONE 3, e3029 (2008).
Yoon, B.E. et al. The amount of astrocytic GABA positively correlates with the degree of tonic inhibition in hippocampal CA1 and cerebellum. Mol. Brain 4, 42 (2011).
Borchelt, D.R. et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939–945 (1997).
Kamphuis, W. et al. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS ONE 7, e42823 (2012).
Volianskis, A., Køstner, R., Mølgaard, M., Hass, S. & Jensen, M.S. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1δE9-deleted transgenic mice model of β-amyloidosis. Neurobiol. Aging 31, 1173–1187 (2010).
Irizarry, M.C. et al. Aβ deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J. Neurosci. 17, 7053–7059 (1997).
Matousek, S.B. et al. Chronic IL-1β–mediated neuroinflammation mitigates amyloid pathology in a mouse model of Alzheimer's disease without inducing overt neurodegeneration. J. Neuroimmune Pharmacol. 7, 156–164 (2012).
Hartlage-Rübsamen, M. et al. Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms. Acta Neuropathol. 121, 705–719 (2011).
Kesner, R.P. A behavioral analysis of dentate gyrus function. Prog. Brain Res. 163, 567–576 (2007).
Nakashiba, T. et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149, 188–201 (2012).
Cao, D., Lu, H., Lewis, T.L. & Li, L. Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J. Biol. Chem. 282, 36275–36282 (2007).
Han, K.-S. et al. Channel-mediated astrocytic glutamate release via Bestrophin-1 targets synaptic NMDARs. Mol. Brain 6, 4 (2013).
Park, H. et al. High glutamate permeability and distal localization of Best1 channel in CA1 hippocampal astrocyte. Mol. Brain 6, 54 (2013).
Seiler, N., Sshmidt-Glenewinkel, T. & Sarhan, S. On the formation of γ-aminobutyric acid from putrescine in brain. J. Biochem. 86, 277–279 (1979).
Laschet, J., Grisar, T., Bureau, M. & Guillaume, D. Characteristics of putrescine uptake and subsequent GABA formation in primary cultured astrocytes from normal C57BL/6J and epileptic DBA/2J mouse brain cortices. Neuroscience 48, 151–157 (1992).
Caspi, R. et al. The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res. 40, D742–D753 (2012).
Seiler, N. & Al-Therib, M. Putrescine catabolism in mammalian brain. Biochem. J. 144, 29–35 (1974).
Saura, J. et al. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 62, 15–30 (1994).
Nakamura, S. et al. Expression of monoamine oxidase B activity in astrocytes of senile plaques. Acta Neuropathol. 80, 419–425 (1990).
Saura, J., Kettler, R., Da Prada, M. & Richards, J. Quantitative enzyme radioautography with 3H-Ro 41–1049 and 3H-Ro 19–6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain. J. Neurosci. 12, 1977–1999 (1992).
Levitt, P., Pintar, J.E. & Breakefield, X.O. Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotonergic neurons. Proc. Natl. Acad. Sci. USA 79, 6385–6389 (1982).
Birkmayer, W., Riederer, P., Youdim, M. & Linauer, W. The potentiation of the anti akinetic effect after L-dopa treatment by an inhibitor of MAO-B, Deprenil. J. Neural Transm. 36, 303–326 (1975).
Youdim, M.B. et al. Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J. Neurosci. Res. 79, 172–179 (2005).
Nägga, K., Bogdanovic, N. & Marcusson, J. GABA transporters (GAT-1) in Alzheimer's disease. J. Neural Transm. 106, 1141–1149 (1999).
Lee, J., Kannagi, M., Ferrante, R.J., Kowall, N.W. & Ryu, H. Activation of Ets-2 by oxidative stress induces Bcl-xL expression and accounts for glial survival in amyotrophic lateral sclerosis. FASEB J. 23, 1739–1749 (2009).
Turrigiano, G.G. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435 (2008).
Allen, C. & Stevens, C.F. An evaluation of causes for unreliability of synaptic transmission. Proc. Natl. Acad. Sci. USA 91, 10380–10383 (1994).
Gimbel, D.A. et al. Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J. Neurosci. 30, 6367–6374 (2010).
De Angelis, L. & Furlan, C. The anxiolytic-like properties of two selective MAOIs, moclobemide and selegiline, in a standard and an enhanced light/dark aversion test. Pharmacol. Biochem. Behav. 65, 649–653 (2000).
Wilcock, G.K., Birks, J., Whitehead, A. & Evans, S.J. The effect of selegiline in the treatment of people with Alzheimer's disease: a meta-analysis of published trials. Int. J. Geriatr. Psychiatry 17, 175–183 (2002).
Engberg, G., Elebring, T. & Nissbrandt, H. Deprenyl (selegiline), a selective MAO-B inhibitor with active metabolites; effects on locomotor activity, dopaminergic neurotransmission and firing rate of nigral dopamine neurons. J. Pharmacol. Exp. Ther. 259, 841–847 (1991).
Marzo, A. et al. Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. Pharmacol. Res. 50, 77–85 (2004).
Squire, L.R., Stark, C.E. & Clark, R.E. The medial temporal lobe*. Annu. Rev. Neurosci. 27, 279–306 (2004).
Palop, J.J., Chin, J. & Mucke, L. A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768–773 (2006).
Pike, C.J., Cummings, B., Monzavi, R. & Cotman, C.W. β-amyloid–induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer's disease. Neuroscience 63, 517–531 (1994).
Chen, G. et al. A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease. Nature 408, 975–979 (2000).
Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).
Scheff, S.W. & Price, D.A. Synaptic density in the inner molecular layer of the hippocampal dentate gyrus in Alzheimer disease. J. Neuropathol. Exp. Neurol. 57, 1146–1153 (1998).
Jacobs, K., Kharazia, V.N. & Prince, D.A. Mechanisms underlying epileptogenesis in cortical malformations. Epilepsy Res. 36, 165–188 (1999).
Verret, L. et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149, 708–721 (2012).
Piccinin, G.L., Finali, G. & Piccirilli, M. Neuropsychological effects of L-deprenyl in Alzheimer's type dementia. Clin. Neuropharmacol. 13, 147–163 (1990).
Tariot, P.N. et al. L-deprenyl in Alzheimer's disease: preliminary evidence for behavioral change with monoamine oxidase B inhibition. Arch. Gen. Psychiatry 44, 427–433 (1987).
Monteverde, A., Gnemmi, P., Rossi, F. & Finali, G. Selegiline in the treatment of mild to moderate Alzheimer-type dementia. Clin. Ther. 12, 315–322 (1990).
Birks, J. & Flicker, L. Selegiline for Alzheimer's disease. Cochrane Database Syst. Rev. CD000442 (2003).
Gerlach, M., Youdim, M. & Riederer, P. Pharmacology of selegiline. Neurology 47, S137–S145 (1996).
Barres, B.A. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60, 430–440 (2008).
Paxinos, G. & Franklin, K. The Mouse Brain in Stereotaxic Coordinates: Compact Second Edition. (Academic Press, San Diego, 2003).
Kutlán, D. & Molnar-Perl, I. New aspects of the simultaneous analysis of amino acids and amines as their o-phthaldialdehyde derivatives by high-performance liquid chromatography. Analysis of wine, beer and vinegar. J. Chromatogr. A 987, 311–322 (2003).
Mengerink, Y., Kutlan, D., Toth, F., Csampai, A. & Molnar-Perl, I. Advances in the evaluation of the stability and characteristics of the amino acid and amine derivatives obtained with the o-phthaldialdehyde/3-mercaptopropionic acid and o-phthaldialdehyde/N-acetyl-L-cysteine reagents. High-performance liquid chromatography-mass spectrometry study. J. Chromatogr. A 949, 99–124 (2002).
Kim, Y.S., Moss, J.A. & Janda, K.D. Biological tuning of synthetic tactics in solid-phase synthesis: Application to Aβ (1–42). J. Org. Chem. 69, 7776–7778 (2004).
Unal Cevik, I. & Dalkara, T. Intravenously administered propidium iodide labels necrotic cells in the intact mouse brain after injury. Cell Death Differ. 10, 928–929 (2003).
Park, H. et al. Bestrophin-1 encodes for the Ca2+-activated anion channel in hippocampal astrocytes. J. Neurosci. 29, 13063–13073 (2009).
Fujiwara, K., Tanabe, T., Yabuuchi, M., Ueoka, R. & Tsuru, D. A monoclonal antibody against the glutaraldehyde-conjugated polyamine, putrescine: application to immunocytochemistry. Histochem. Cell Biol. 115, 471–477 (2001).
Sehgal, N. et al. Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc. Natl. Acad. Sci. USA 109, 3510–3515 (2012).
Hong, J. et al. Microglial Toll-like receptor 2 contributes to kainic acid-induced glial activation and hippocampal neuronal cell death. J. Biol. Chem. 285, 39447–39457 (2010).
Livak, K.J. & Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25, 402–408 (2001).
Acknowledgements
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.
Author information
Authors and Affiliations
Contributions
S.J., O.Y., D.K. and C.J.L. designed the study, analyzed the data and wrote the manuscript. O.Y. carried out most slice electrophysiology. Y.J.H., N.W.K. and H.R. performed human tissue experiments. Y.E.C. and D.H.W. performed sniffer patch. S.J., M.P. and J.C. performed behavior tests. J.Y.B. and Y.C.B. performed electron microscopy experiments. S.J., J.L. and H.C. contributed to GABA recording. H.J.P. and I.S. performed microdialysis and HPLC. E.H., D.Y.L. and J.H. contributed to molecular biology. H.Y.K. and Y.K. synthesized Aβ42 and performed oligomer western blotting. B.-E.Y. contributed to lentiviral Maob shRNA cloning. Y.J. contributed to discussion and to mouse breeding. S.J. conducted all the rest of the experiments with assistance from T.K., S.-J.O., S.J.P. and H.L. All authors contributed to analysis and discussion of the results.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–9 and Supplementary Tables 1–3 (PDF 3928 kb)
Rights and permissions
About this article
Cite this article
Jo, S., Yarishkin, O., Hwang, Y. et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. Nat Med 20, 886–896 (2014). https://doi.org/10.1038/nm.3639
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.3639
- Springer Nature America, Inc.
This article is cited by
-
Exercise mimetics: a novel strategy to combat neuroinflammation and Alzheimer’s disease
Journal of Neuroinflammation (2024)
-
The role of NLRP3 inflammasome in aging and age-related diseases
Immunity & Ageing (2024)
-
A Key Mediator and Imaging Target in Alzheimer’s Disease: Unlocking the Role of Reactive Astrogliosis Through MAOB
Nuclear Medicine and Molecular Imaging (2024)
-
Polyamines: their significance for maintaining health and contributing to diseases
Cell Communication and Signaling (2023)
-
Molecular insights into sex-specific metabolic alterations in Alzheimer’s mouse brain using multi-omics approach
Alzheimer's Research & Therapy (2023)