Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss
Open accessAbstract
Significance: Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we describe a pathway for synaptic damage whereby amyloid-β 1–42 peptide (Aβ 1–42 ) releases, via stimulation of α7 nicotinic receptors, excessive amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA-type glutamate receptors (eNMDARs) to mediate synaptic damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced synaptic loss, providing hope for disease-modifying intervention in AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [117]
The Discussion reports that oligomeric Aβ induces excessive glutamate release from astrocytes, activating extrasynaptic NMDA receptors and contributing to synaptic damage. The FRET-Based Imaging section does not establish glutamate release by microglia; it reports that removing microglia did not change the measured release. The GABA-producing-astrocyte clause has different citations and is not attributed to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredUp-regulation of α7 nicotinic acetylcholine receptors in astrocytes causes abnormal astrocytic Ca2+ elevations and massive glutamate release.
“Up-regulated receptors included α7 nicotinic Ach receptors 94 , Ca 2+ -permeant ligand-gated channels whose up-regulation causes abnormal astrocytic Ca 2+ elevations and massive glutamate release 95, 96”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [96]
Aβ42 oligomers released from neurons bind directly to α7nAChRs in adjacent astrocytes, inducing astrocytic glutamate release.
“In addition, Aβ42 oligomers released from neurons can bind directly to α7nAChRs in adjacent astrocytes, thereby inducing astrocytic glutamate release [380].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [380]
Neuronal FcγRIIb binds Aβ42 with high affinity and mediates neurotoxicity and memory impairment triggered by Aβ.
“Neuronal FcγRIIb can bind to Aβ42 with a high affinity, and mediate neurotoxicity and memory impairment triggered by Aβ [240, 376–380].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [380]
Excreted glutamate activates extrasynaptic NMDARs in neurons within neuron/astrocyte conjugates, triggering mitochondrial dysfunction, caspase 3 activation, tau hyperphosphorylation, NO/ROS/VEGF production, and dendritic spine/synaptic damage.
“Excreted glutamate can activate extrasynaptic NMDAR in neurons residing within neuron/astrocyte conjugates, resulting in Ca2+ efflux. This triggers multiple events, including mitochondrial dysfunction, caspase 3 activation, tau hyperphosphorylation, and excessive production of NO, ROS and VEG-F. These events result in damage to dendritic spines and neuronal synapses, disrupting neuronal/astrocytic”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [380]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., et al. (2008) · Nature Medicine · doi:10.1038/nm1782 · Cited by 3,685 · see citing works
Lipton, S. A., Choi, Y.-B., Pan, Z.-H., Lei, S. Z., Chen, H.-S. V., Sucher, N. J., Loscalzo, J., Singel, D. J., & Stamler, J. S. (1993) · Nature · doi:10.1038/364626a0 · Cited by 2,433 · see citing works
Self-citationNitric oxide mediates glutamate neurotoxicity in primary cortical cultures.
Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S., & Snyder, S. H. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.14.6368 · Cited by 2,174 · see citing works
A more efficient method to generate integration-free human iPS cells
Okita, K., Matsumura, Y., Sato, Y., Okada, A., Morizane, A., Okamoto, S., Hong, H., Nakagawa, M., Tanabe, K., Tezuka, K.-I., et al. (2011) · Nature Methods · doi:10.1038/nmeth.1591 · Cited by 2,061 · see citing works
Self-citationReducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892 · see citing works
Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
Ittner, L. M., Ke, Y. D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., Wölfing, H., Chieng, B. C., Christie, M. J., Napier, I. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.036 · Cited by 1,821 · see citing works
Glutamate-mediated astrocyte–neuron signalling
Parpura, V., Basarsky, T. A., Liu, F., Jeftinija, K., Jeftinija, S., & Haydon, P. G. (1994) · Nature · doi:10.1038/369744a0 · Cited by 1,737 · see citing works
Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
Hardingham, G. E., Fukunaga, Y., & Bading, H. (2002) · Nature Neuroscience · doi:10.1038/nn835 · Cited by 1,686 · see citing works
Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks
Palop, J. J., & Mucke, L. (2010) · Nature Neuroscience · doi:10.1038/nn.2583 · Cited by 1,651 · see citing works
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
Hardingham, G. E., & Bading, H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2911 · Cited by 1,644 · see citing works
Shankar, G. M., Bloodgood, B. L., Townsend, M., Walsh, D. M., Selkoe, D. J., & Sabatini, B. L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4970-06.2007 · Cited by 1,592 · see citing works
Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., Pitstick, R., Carlson, G. A., Lanier, L. M., Yuan, L.-L., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.030 · Cited by 1,118 · see citing works
S-Nitrosylation of Drp1 Mediates β-Amyloid-Related Mitochondrial Fission and Neuronal Injury
Cho, D.-H., Nakamura, T., Fang, J., Cieplak, P., Godzik, A., Gu, Z., & Lipton, S. A. (2009) · Science · doi:10.1126/science.1171091 · Cited by 1,092 · see citing works
Self-citationNeuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons
Scheiffele, P., Fan, J., Choih, J., Fetter, R., & Serafini, T. (2000) · Cell · doi:10.1016/s0092-8674(00)80877-6 · Cited by 1,060 · see citing works
AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss
Hsieh, H., Boehm, J., Sato, C., Iwatsubo, T., Tomita, T., Sisodia, S., & Malinow, R. (2006) · Neuron · doi:10.1016/j.neuron.2006.10.035 · Cited by 1,042 · see citing works
Li, S., Hong, S., Shepardson, N. E., Walsh, D. M., Shankar, G. M., & Selkoe, D. (2009) · Neuron · doi:10.1016/j.neuron.2009.05.012 · Cited by 972 · see citing works
Morris, M., Maeda, S., Vossel, K., & Mucke, L. (2011) · Neuron · doi:10.1016/j.neuron.2011.04.009 · Cited by 899 · see citing works
Jin, M., Shepardson, N., Yang, T., Chen, G., Walsh, D., & Selkoe, D. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017033108 · Cited by 876 · see citing works
β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity
Wang, H.-Y., Lee, D. H. S., D’Andrea, M. R., Peterson, P. A., Shank, R. P., & Reitz, A. B. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5626 · Cited by 818 · see citing works
Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists
Papouin, T., Ladépêche, L., Ruel, J., Sacchi, S., Labasque, M., Hanini, M., Groc, L., Pollegioni, L., Mothet, J., & Oliet, S. H. R. (2012) · Cell · doi:10.1016/j.cell.2012.06.029 · Cited by 752 · see citing works
Neurotransmitter regulation of neuronal outgrowth, plasticity and survival
Lipton, S. A., & Kater, S. B. (1989) · Trends in Neurosciences · doi:10.1016/0166-2236(89)90026-x · Cited by 724 · see citing works
Self-citationMassey, P. V., Johnson, B. E., Moult, P. R., Auberson, Y. P., Brown, M. W., Molnár, E., Collingridge, G. L., & Bashir, Z. I. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1697-04.2004 · Cited by 693 · see citing works
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2357-10.2010 · Cited by 686 · see citing works
Lee, H.-K., Kameyama, K., Huganir, R. L., & Bear, M. F. (1998) · Neuron · doi:10.1016/s0896-6273(00)80632-7 · Cited by 668 · see citing works
Li, S., Jin, M., Koeglsperger, T., Shepardson, N. E., Shankar, G. M., & Selkoe, D. J. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0203-11.2011 · Cited by 664 · see citing works
Roberson, E. D., Halabisky, B., Yoo, J. W., Yao, J., Chin, J., Yan, F., Wu, T., Hamto, P., Devidze, N., Yu, G.-Q., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4152-10.2011 · Cited by 654 · see citing works
Patneau, D. K., & Mayer, M. (1990) · Journal of Neuroscience · doi:10.1523/jneurosci.10-07-02385.1990 · Cited by 653 · see citing works
Nonuniform probability of glutamate release at a hippocampal synapse.
Rosenmund, C., Clements, J., & Westbrook, G. (1993) · Science · doi:10.1126/science.7901909 · Cited by 616 · see citing works
A chemical platform for improved induction of human iPSCs
Lin, T., Ambasudhan, R., Xu, Y., Li, W., Hilcove, S. A., Abujarour, R., Lin, X., Hahm, H. S., Hao, E., Hayek, A., et al. (2009) · Nature Methods · doi:10.1038/nmeth.1393 · Cited by 596 · see citing works
Self-citationCaspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease
D'Amelio, M., Cavallucci, V., Middei, S., Marchetti, C., Pacioni, S., Ferri, A., Diamantini, A., De Zio, D., Carrara, P., Battistini, L., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2709 · Cited by 572 · see citing works
Milnerwood, A. J., Gladding, C. M., Pouladi, M. A., Kaufman, A. M., Hines, R. M., Boyd, J. D., Ko, R. W. Y., Vasuta, O. C., Graham, R. K., Hayden, M. R., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.01.008 · Cited by 516 · see citing works
Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses
Abramov, E., Dolev, I., Fogel, H., Ciccotosto, G. D., Ruff, E., & Slutsky, I. (2009) · Nature Neuroscience · doi:10.1038/nn.2433 · Cited by 499 · see citing works
Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses
Papadia, S., Soriano, F. X., Léveillé, F., Martel, M.-A., Dakin, K. A., Hansen, H. H., Kaindl, A., Sifringer, M., Fowler, J., Stefovska, V., et al. (2008) · Nature Neuroscience · doi:10.1038/nn2071 · Cited by 498 · see citing works
Deleterious Effects of Amyloid β Oligomers Acting as an Extracellular Scaffold for mGluR5
Renner, M., Lacor, P. N., Velasco, P. T., Xu, J., Contractor, A., Klein, W. L., & Triller, A. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.029 · Cited by 468 · see citing works
Alzheimer's disease: Aβ, tau and synaptic dysfunction
LaFerla, F. M., & Oddo, S. (2005) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2005.02.009 · Cited by 461 · see citing works
Okamoto, S., Pouladi, M. A., Talantova, M. V., Yao, D., Xia, P., Ehrnhoefer, D. E., Zaidi, R., Clemente, A., Kaul, M., Graham, R. K., et al. (2009) · Nature Medicine · doi:10.1038/nm.2056 · Cited by 439 · see citing works
Self-citationReversing EphB2 depletion rescues cognitive functions in Alzheimer model
Cissé, M., Halabisky, B., Harris, J., Devidze, N., Dubal, D. B., Sun, B., Orr, A., Lotz, G., Kim, D. H., Hamto, P., et al. (2011) · Nature · doi:10.1038/nature09635 · Cited by 433 · see citing works
Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation
Choi, Y., Tenneti, L., Le, D. A., Ortiz, J., Bai, G., Chen, H.-S. V., & Lipton, S. A. (2000) · Nature Neuroscience · doi:10.1038/71090 · Cited by 426 · see citing works
Self-citationTomiyama, T., Matsuyama, S., Iso, H., Umeda, T., Takuma, H., Ohnishi, K., Ishibashi, K., Teraoka, R., Sakama, N., Yamashita, T., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5825-09.2010 · Cited by 396 · see citing works
Neuroinflammation and regulation of glial glutamate uptake in neurological disorders
Tilleux, S., & Hermans, E. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21325 · Cited by 381 · see citing works
Xia, P., Chen, H.-S. V., Zhang, D., & Lipton, S. A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2488-10.2010 · Cited by 380 · see citing works
Self-citationOrellana, J. A., Froger, N., Ezan, P., Jiang, J. X., Bennett, M. V. L., Naus, C. C. G., Giaume, C., & Sáez, J. C. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07210.x · Cited by 379 · see citing works
Glutamate induces de novo growth of functional spines in developing cortex
Kwon, H.-B., & Sabatini, B. L. (2011) · Nature · doi:10.1038/nature09986 · Cited by 368 · see citing works
Amyloid beta from axons and dendrites reduces local spine number and plasticity
Wei, W., Nguyen, L. N., Kessels, H. W., Hagiwara, H., Sisodia, S., & Malinow, R. (2010) · Nature Neuroscience · doi:10.1038/nn.2476 · Cited by 357 · see citing works
Sharma, G. G., & Vijayaraghavan, S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.071540198 · Cited by 351 · see citing works
Aβ1-42 inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β
Jo, J., Whitcomb, D. J., Olsen, K. M., Kerrigan, T. L., Lo, S.-C., Bru-Mercier, G., Dickinson, B., Scullion, S., Sheng, M., Collingridge, G., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2785 · Cited by 305 · see citing works
Sydow, A., Van der Jeugd, A., Zheng, F., Ahmed, T., Balschun, D., Petrova, O., Drexler, D., Zhou, L., Rune, G., Mandelkow, E., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5245-10.2011 · Cited by 302 · see citing works
Hires, S. A., Zhu, Y., & Tsien, R. Y. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712008105 · Cited by 293 · see citing works
Self-citationSong, P., Mabrouk, O. S., Hershey, N. D., & Kennedy, R. T. (2011) · Analytical Chemistry · doi:10.1021/ac202794q · Cited by 235 · see citing works
Rosenberg, D., Artoul, S., Segal, A. C., Kolodney, G., Radzishevsky, I. S., Dikopoltsev, E., Foltyn, V. N., Inoue, R., Mori, H., Billard, J., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3836-12.2013 · Cited by 228 · see citing works
Self-citationMatos, M., Augusto, E., Oliveira, C. R., & Agostinho, P. M. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.08.022 · Cited by 223 · see citing works
Kurup, P. K., Zhang, Y., Xu, J., Venkitaramani, D. V., Haroutunian, V. H., Greengard, P., Nairn, A. C., & Lombroso, P. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0157-10.2010 · Cited by 222 · see citing works
Shleper, M., Kartvelishvily, E., & Wolosker, H. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3190-05.2005 · Cited by 216 · see citing works
Self-citationDziewczapolski, G., Głogowski, M., Masliah, E., & Heinemann, S. F. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.6159-08.2009 · Cited by 197 · see citing works
Self-citationBordji, K., Becerril-Ortega, J., Nicole, O., & Buisson, A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.3021-10.2010 · Cited by 195 · see citing works
S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide
Qu, J. T., Nakamura, T., Cao, G., Holland, E. A., McKercher, S. R., & Lipton, S. A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105172108 · Cited by 185 · see citing works
Self-citationTampellini, D., Capetillo‐Zarate, E., Dumont, M., Huang, Z., Yu, F., Lin, M. T. S., & Gouras, G. K. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.3383-10.2010 · Cited by 161 · see citing works
Synaptic NMDA Receptors Mediate Hypoxic Excitotoxic Death
Wroge, C. M., Hogins, J., Eisenman, L., & Mennerick, S. J. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6371-11.2012 · Cited by 142 · see citing works
Song, M.-S., Rauw, G. A., Baker, G. B., & Kar, S. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06498.x · Cited by 140 · see citing works
Tampellini, D., Rahman, N., Gallo, E. F., Huang, Z., Dumont, M., Capetillo-Zarate, E., Ma, T., Zheng, R., Lu, B., Nanus, D. M., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2292-09.2009 · Cited by 127 · see citing works
Usui, K., Hulleman, J. D., Paulsson, J. F., Siegel, S. J., Powers, E. T., & Kelly, J. W. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804758106 · Cited by 84 · see citing works
Self-citationMaskell, P., Spéder, P., Newberry, N. R., & Bermúdez, I. (2003) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705559 · Cited by 80 · see citing works
Opposing Synaptic Regulation of Amyloid-β Metabolism by NMDA Receptors <i>In Vivo</i>
Verges, D. K., Restivo, J. L., Goebel, W. D., Holtzman, D. M., & Cirrito, J. R. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0607-11.2011 · Cited by 74 · see citing works
Abdallah, L. E., Bonasera, S. J., Hopf, F. W., O'Dell, L., Giorgetti, M., Jongsma, M., Carra, S., Pierucci, M., Giovanni, G. D., Esposito, E., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3905-08.2009 · Cited by 62 · see citing works
Self-citationKollen, M., Dutar, P., & Jouvenceau, A. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.04.045 · Cited by 44 · see citing works
Caspase activation without apoptosis: insight into Aβ initiation of neurodegeneration
Hyman, B. T. (2010) · Nature Neuroscience · doi:10.1038/nn0111-5 · Cited by 34 · see citing works
The Pharmacology of Aminoadamantane Nitrates
Wang, Y., Eu, J. P., Washburn, M. S., Gong, T., Chen, H.-S. V., James, W. L., Lipton, S. A., Stamler, J. S., Went, G. T., & Porter, S. (2006) · Current Alzheimer Research · doi:10.2174/156720506777632808 · Cited by 34 · see citing works
Self-citationDistribution of Extracellular Glutamate in the Neuropil of Hippocampus
Herman, M. A., Nahir, B., & Jahr, C. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026501 · Cited by 31 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
A review on Alzheimer's disease pathophysiology and its management: an update
Kumar, A., Singh, A., & Ekavali (2015) · Pharmacological Reports · doi:10.1016/j.pharep.2014.09.004 · Cited by 1,578 · see citing works
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
Self-citationAmyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
“Aβ-induced LTD is also caused by inhibiting glutamate uptake and stimulating glutamate releasing, which evently elevates glutamate levels in the synapse cleft.(222,225,227,228) An increase of glutamate activated GluN2B-bearing NMDARs, which further led to calcium-induced LTD and synaptic depression.”
BackgroundSelf-citationAstrocyte function from information processing to cognition and cognitive impairment
Santello, M., Toni, N., & Volterra, A. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0325-8 · Cited by 737 · see citing works
The road to restoring neural circuits for the treatment of Alzheimer's disease
Canter, R. G., Penney, J., & Tsai, L.-H. (2016) · Nature · doi:10.1038/nature20412 · Cited by 565 · see citing works
Lee, S. J. C., Nam, E., Lee, H. J., Savelieff, M. G., & Lim, M. H. (2017) · Chemical Society Reviews · doi:10.1039/c6cs00731g · Cited by 576 · see citing works
Elusive roles for reactive astrocytes in neurodegenerative diseases
Ben Haim, L., Carrillo-de Sauvage, M.-A., Ceyzériat, K., & Escartin, C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00278 · Cited by 453 · see citing works
Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders
Brandebura, A. N., Paumier, A., Onur, T. S., & Allen, N. J. (2023) · Nature Reviews Neuroscience · doi:10.1038/s41583-022-00641-1 · Cited by 427 · see citing works
Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students
Lepeta, K., Lourenco, M. V., Schweitzer, B. C., Martino Adami, P. V., Banerjee, P., Catuara‐Solarz, S., de La Fuente Revenga, M., Guillem, A. M., Haidar, M., Ijomone, O. M., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13713 · Cited by 386 · see citing works
Self-citationJeremic, D., Jiménez-Díaz, L., & Navarro-López, J. D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101496 · Cited by 306 · see citing works
Dysfunction of NMDA receptors in Alzheimer’s disease
Zhang, Y., Li, P., Feng, J., & Wu, M. (2016) · Neurological Sciences · doi:10.1007/s10072-016-2546-5 · Cited by 282 · see citing works
“A b induces glutamate release from astrocytes, which in turn activates extrasy-naptic NMDARs on neurons and subsequent decrease in miniature excitatory postsynaptic currents (mEPSCs) which may reflect early synaptic injury [30].”
BackgroundSynaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic strategies
Chen, Y., Fu, A. K. Y., & Ip, N. Y. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.11.006 · Cited by 258 · see citing works
Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease
Overk, C. R., & Masliah, E. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.015 · Cited by 242 · see citing works
Self-citationOchalek, A., Mihalik, B., Avci, H. X., Chandrasekaran, A., Téglási, A., Bock, I., Giudice, M. L., Táncos, Z., Molnár, K., László, L., et al. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0317-z · Cited by 225 · see citing works
Combination Drug Therapy for the Management of Alzheimer’s Disease
Kabir, M. T., Uddin, M. S., Mamun, A. A., Jeandet, P., Aleya, L., Mansouri, R. A., Ashraf, G. M., Mathew, B., Bin-Jumah, M. N., & Abdel-Daim, M. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093272 · Cited by 217 · see citing works
Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease
Govindpani, K., Calvo-Flores Guzmán, B., Vinnakota, C., Waldvogel, H., Faull, R., & Kwakowsky, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081813 · Cited by 208 · see citing works
Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β
Vossel, K. A., Xu, J. C., Fomenko, V., Miyamoto, T., Suberbielle, E., Knox, J. A., Ho, K., Kim, D. H., Yu, G.-Q., & Mucke, L. (2015) · Journal of Cell Biology · doi:10.1083/jcb.201407065 · Cited by 167 · see citing works
ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
Lane-Donovan, C., & Herz, J. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.12.001 · Cited by 157 · see citing works
Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases
Nakamura, T., Prikhodko, O. A., Pirie, E., Nagar, S., Akhtar, M. W., Oh, C.-K., McKercher, S. R., Ambasudhan, R., Okamoto, S.-I., & Lipton, S. A. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.03.017 · Cited by 165 · see citing works
Self-citationBalducci, C., Frasca, A., Zotti, M., La Vitola, P., Mhillaj, E., Grigoli, E., Iacobellis, M., Grandi, F., Messa, M., Colombo, L., et al. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.10.012 · Cited by 164 · see citing works
More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158 · see citing works
Uddin, M. S., Rahman, M. M., Jakaria, M., Rahman, M. S., Hossain, M. S., Islam, A., Ahmed, M., Mathew, B., Omar, U. M., Barreto, G. E., et al. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01911-8 · Cited by 156 · see citing works
Herbert, J., & Lucassen, P. J. (2016) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2015.12.001 · Cited by 150 · see citing works
Astrocyte Intermediaries of Septal Cholinergic Modulation in the Hippocampus
Pabst, M., Braganza, O., Dannenberg, H., Hu, W., Pothmann, L., Rosen, J., Mody, I., van Loo, K., Deisseroth, K., Becker, A. J., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.003 · Cited by 123 · see citing works
Neuron–astrocyte signaling is preserved in the aging brain
Gómez‐Gonzalo, M., Martin‐Fernandez, M., Martínez‐Murillo, R., Mederos, S., Hernández‐Vivanco, A., Jamison, S., Fernandez, A. P., Serrano, J., Calero, P., Futch, H. S., et al. (2017) · Glia · doi:10.1002/glia.23112 · Cited by 114 · see citing works
Astrocyte–neuron interplay in maladaptive plasticity.
Papa, M., De Luca, C., Petta, F., Alberghina, L., & Cirillo, G. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.01.010 · Cited by 104 · see citing works
Trudler, D., Sanz-Blasco, S., Eisele, Y. S., Ghatak, S., Bodhinathan, K., Akhtar, M. W., Lynch, W. P., Piña-Crespo, J. C., Talantova, M., Kelly, J. W., et al. (2021) · The Journal of Neuroscience · doi:10.1523/jneurosci.1871-20.2020 · Cited by 104 · see citing works
Self-citationPICALM and Alzheimer’s Disease: An Update and Perspectives
Ando, K., Nagaraj, S., Küçükali, F., de Fisenne, M.-A., Kosa, A.-C., Doeraene, E., Lopez Gutierrez, L., Brion, J.-P., & Leroy, K. (2022) · Cells · doi:10.3390/cells11243994 · Cited by 104 · see citing works
Pirttimaki, T. M., Codadu, N. K., Awni, A., Pratik, P., Nagel, D. A., Hill, E. J., Dineley, K. T., & Parri, H. R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081828 · Cited by 103 · see citing works
The role of astrocytic α7 nicotinic acetylcholine receptors in Alzheimer disease
Fontana, I. C., Kumar, A., & Nordberg, A. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00792-4 · Cited by 86 · see citing works
Cai, W., Li, L., Sang, S., Pan, X., & Zhong, C. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-022-00985-9 · Cited by 83 · see citing works
Uddin, M. S., Al Mamun, A., Kabir, M. T., Ashraf, G. M., Bin-Jumah, M. N., & Abdel-Daim, M. M. (2021) · Molecular Neurobiology · doi:10.1007/s12035-020-02116-9 · Cited by 86 · see citing works
Ca2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease
McDaid, J., Mustaly-Kalimi, S., & Stutzmann, G. E. (2020) · Cells · doi:10.3390/cells9122655 · Cited by 73 · see citing works
Xu, Z.-Q., Zhang, W.-J., Su, D.-F., Zhang, G.-Q., & Miao, C.-Y. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-273 · Cited by 60 · see citing works
Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease
Chiarini, A., Armato, U., Liu, D., & Dal Prà, I. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00134 · Cited by 51 · see citing works
Riebe, I., Seth, H., Culley, G., Dósa, Z., Radi, S., Strand, K., Fröjd, V., & Hanse, E. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13128 · Cited by 40 · see citing works
Reelin proteolysis affects signaling related to normal synapse function and neurodegeneration
Lussier, A. L., Weeber, E. J., & Rebeck, G. W. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00075 · Cited by 31 · see citing works
Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer’s disease
Wu, L., Zhou, X., Cao, Y., MAK, S. H., Zha, L., Li, N., Su, Z., Han, Y., Wang, Y., Man Hoi, M. P., et al. (2021) · Aging Cell · doi:10.1111/acel.13371 · Cited by 24 · see citing works
Self-citationRole of Ion Channels in Alzheimer’s Disease Pathophysiology
Bhoi, R., Mitra, T., Tejaswi, K., Manoj, V., & Ghatak, S. (2025) · The Journal of Membrane Biology · doi:10.1007/s00232-025-00341-8 · Cited by 19 · see citing works
Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome
Caraci, F., Iulita, M. F., Pentz, R., Flores Aguilar, L., Orciani, C., Barone, C., Romano, C., Drago, F., & Cuello, A. C. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.10.004 · Cited by 18 · see citing works
Amyloid-β Impairs Vesicular Secretion in Neuronal and Astrocyte Peptidergic Transmission
Plá, V., Barranco, N., Pozas, E., & Aguado, F. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00202 · Cited by 13 · see citing works
Henao‐Restrepo, J., López‐Murillo, C., Valderrama‐Carmona, P., Orozco‐Santa, N., Gomez, J., Gutiérrez‐Vargas, J., Moraga, R., Toledo, J., Littau, J. L., Härtel, S., et al. (2023) · Brain Pathology · doi:10.1111/bpa.13119 · Cited by 11 · see citing works
The transcriptional and cellular landscape of cognitive resilience to Alzheimer’s disease
Khera, N., Raju, R. M., & Lipton, S. A. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1665802 · Cited by 3 · see citing works
Self-citation
- Authors
- Talantova, M., Sanz-Blasco, S., Zhang, X., Xia, P., Akhtar, M. W., Okamoto, S.-I., Dziewczapolski, G., Nakamura, T., Cao, G., Pratt, A. E., Kang, Y.-J., Tu, S., Molokanova, E., McKercher, S. R., Hires, S. A., Sason, H., Stouffer, D. G., Buczynski, M. W., Solomon, J. P., Michael, S., Powers, E. T., Kelly, J. W., Roberts, A., Tong, G., Fang-Newmeyer, T., Parker, J., Holland, E. A., Zhang, D., Nakanishi, N., Chen, H.-S. V., Wolosker, H., Wang, Y., Parsons, L. H., Ambasudhan, R., Masliah, E., Heinemann, S. F., Piña-Crespo, J. C., & Lipton, S. A.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
- Salk Institute for Biological Studies (US)
- Howard Hughes Medical Institute (US)
- Technion – Israel Institute of Technology (IL)
- Scripps Research Institute (US)
- University of California San Diego (US)
- Jinan University (CN)
- ORCID
- Talantova, Maria
- Xia, Peng
- Okamoto, Shu-ichi
- Dziewczapolski, Gustavo
- Nakamura, Tomohiro
- Molokanova, Elena
- Hires, Samuel Andrew
- Stouffer, David G.
- Buczynski, Matthew W.
- Solomon, James P.
- Michael, Sarah
- Powers, Evan T.
- Kelly, Jeffery W.
- Roberts, Amanda
- Parker, James
- Zhang, Dongxian
- Chen, H.-S. Vincent
- Wolosker, Herman
- Wang, Yuqiang
- Ambasudhan, Rajesh
- Masliah, Eliezer
- Piña-Crespo, Juan C.
- Lipton, Stuart A.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-06-17
- Volume
- 110
- Issue
- 27
- Pages
- E2518-27
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3704025
- OpenAlex
- W2001261203
- Cited by
- 600
- References
- 68
- Citations by year
- 2026: 32 · 2025: 49 · 2024: 41 · 2023: 47 · 2022: 54 · 2021: 52 · 2020: 55 · 2019: 39 · 2018: 36 · 2017: 43 · 2016: 41 · 2015: 66 · 2014: 38 · 2013: 6
- FWCI
- 24.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH1010093, W81XWH)
- American Heart Association
- National Institutes of Health (5r01ag010436-15, W81XWH, DA017259, AG005131)
- National Institute on Alcohol Abuse and Alcoholism (R01AA020404)
- National Institute on Aging (R01 AG-010436, P50AG005131, P01 AG010436)
- National Heart, Lung, and Blood Institute (T35HL007491)
- National Institute on Drug Abuse (P01DA017259)
- National Institute of Neurological Disorders and Stroke (P30NS076411, R01NS050636)
- National Institute of Environmental Health Sciences (P01ES016738)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD29587, P01HD029587)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, extrasynaptic NMDA receptors, alpha7 nicotinic acetylcholine receptor, synaptic loss, Alzheimer's disease, miniature excitatory postsynaptic currents, nitric oxide, tau phosphorylation, caspase-3, hippocampus, synaptic depression, amyloid-beta oligomers
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Female, Hippocampus, Humans, Male, Mice, Transgenic, Neural Inhibition, Peptide Fragments, Receptors, Nicotinic, Synapses, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Glutamic Acid, Coculture Techniques, Fluorescence Resonance Energy Transfer, Mice, Rats, HEK293 Cells, alpha7 Nicotinic Acetylcholine Receptor
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
