{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T04:25:16Z","timestamp":1793852716706,"version":"4.6.1"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Metab"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Astrocytes help protect neurons from potential damage caused by reactive oxygen species (ROS). While ROS can also exert beneficial effects, it remains unknown how neuronal ROS signalling is activated during memory formation, and whether astrocytes play a role in this process. Here we discover an astrocyte-to-neuron H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> signalling cascade in <jats:italic>Drosophila<\/jats:italic> that is essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an increase in intracellular calcium ions, which triggers the generation of extracellular superoxide (O<jats:sub>2<\/jats:sub>\u2022<jats:sup>\u2013<\/jats:sup>) by astrocytic NADPH oxidase. Astrocyte-secreted superoxide dismutase 3 (Sod3) converts O<jats:sub>2<\/jats:sub>\u2022<jats:sup>\u2013<\/jats:sup> to hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>), which is imported into neurons of the olfactory memory centre, the mushroom body, as revealed by in vivo H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> imaging. Notably, Sod3 activity requires copper ions, which are supplied by neuronal amyloid precursor protein. We also find that human amyloid-\u03b2 peptide, implicated in Alzheimer\u2019s disease, inhibits the nAChR\u03b17 astrocytic cholinergic receptor and impairs memory formation by preventing H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> synthesis. These findings may have important implications for understanding the aetiology of Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1038\/s42255-024-01189-3","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T10:03:32Z","timestamp":1737713012000},"page":"321-335","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Astrocyte-to-neuron H2O2 signalling supports long-term memory formation in Drosophila and is impaired in an Alzheimer\u2019s disease model"],"prefix":"10.1038","volume":"7","author":[{"given":"Yasmine","family":"Rabah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4239-4372","authenticated-orcid":false,"given":"Jean-Paul","family":"Berwick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7352-3377","authenticated-orcid":false,"given":"Nisrine","family":"Sagar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Pasquer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8426-4465","authenticated-orcid":false,"given":"Pierre-Yves","family":"Pla\u00e7ais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9976-1763","authenticated-orcid":false,"given":"Thomas","family":"Preat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"1189_CR1","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/s41580-022-00456-z","volume":"23","author":"H Sies","year":"2022","unstructured":"Sies, H. et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat. Rev. Mol. Cell Biol. 23, 499\u2013515 (2022).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"1189_CR2","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1089\/ars.2010.3208","volume":"14","author":"CA Massaad","year":"2011","unstructured":"Massaad, C. A. & Klann, E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid. Redox Signal. 14, 2013\u20132054 (2011).","journal-title":"Antioxid. Redox Signal."},{"key":"1189_CR3","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1146\/annurev-pathol-012513-104651","volume":"9","author":"JD Lambeth","year":"2014","unstructured":"Lambeth, J. D. & Neish, A. S. Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited. Annu. Rev. Pathol. 9, 119\u2013145 (2014).","journal-title":"Annu. Rev. Pathol."},{"key":"1189_CR4","doi-asserted-by":"publisher","first-page":"4516","DOI":"10.1074\/jbc.273.8.4516","volume":"273","author":"E Klann","year":"1998","unstructured":"Klann, E., Roberson, E. D., Knapp, L. T. & Sweatt, J. D. A role for superoxide in protein kinase C activation and induction of long-term potentiation. J. Biol. Chem. 273, 4516\u20134522 (1998).","journal-title":"J. Biol. Chem."},{"key":"1189_CR5","doi-asserted-by":"publisher","first-page":"5908","DOI":"10.1128\/MCB.00269-06","volume":"26","author":"KT Kishida","year":"2006","unstructured":"Kishida, K. T. et al. Synaptic plasticity deficits and mild memory impairments in mouse models of chronic granulomatous disease. Mol. Cell. Biol. 26, 5908\u20135920 (2006).","journal-title":"Mol. Cell. Biol."},{"key":"1189_CR6","doi-asserted-by":"publisher","first-page":"e39393","DOI":"10.7554\/eLife.39393","volume":"7","author":"MC Oswald","year":"2018","unstructured":"Oswald, M. C. et al. Reactive oxygen species regulate activity-dependent neuronal plasticity in Drosophila. eLife 7, e39393 (2018).","journal-title":"eLife"},{"key":"1189_CR7","doi-asserted-by":"publisher","first-page":"641802","DOI":"10.3389\/fncel.2021.641802","volume":"15","author":"S Dhawan","year":"2021","unstructured":"Dhawan, S. et al. Reactive oxygen species mediate activity-regulated dendritic plasticity through NADPH oxidase and aquaporin regulation. Front. Cell. Neurosci. 15, 641802 (2021).","journal-title":"Front. Cell. Neurosci."},{"key":"1189_CR8","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1023\/A:1021673703129","volume":"28","author":"ED Levin","year":"1998","unstructured":"Levin, E. D. et al. Molecular manipulations of extracellular superoxide dismutase: functional importance for learning. Behav. Genet. 28, 381\u2013390 (1998).","journal-title":"Behav. Genet."},{"key":"1189_CR9","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/s41593-018-0325-8","volume":"22","author":"M Santello","year":"2019","unstructured":"Santello, M., Toni, N. & Volterra, A. Astrocyte function from information processing to cognition and cognitive impairment. Nat. Neurosci. 22, 154\u2013166 (2019).","journal-title":"Nat. Neurosci."},{"key":"1189_CR10","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/s42255-018-0031-6","volume":"1","author":"C Vicente-Gutierrez","year":"2019","unstructured":"Vicente-Gutierrez, C. et al. Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour. Nat. Metab. 1, 201\u2013211 (2019).","journal-title":"Nat. Metab."},{"key":"1189_CR11","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","volume":"20","author":"DA Butterfield","year":"2019","unstructured":"Butterfield, D. A. & Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci. 20, 148\u2013160 (2019).","journal-title":"Nat. Rev. Neurosci."},{"key":"1189_CR12","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.3233\/JAD-161088","volume":"57","author":"E T\u00f6nnies","year":"2017","unstructured":"T\u00f6nnies, E. & Trushina, E. Oxidative stress, synaptic dysfunction, and Alzheimer\u2019s disease. J. Alzheimers Dis. JAD 57, 1105\u20131121 (2017).","journal-title":"J. Alzheimers Dis. JAD"},{"key":"1189_CR13","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1038\/nn.4018","volume":"18","author":"ES Musiek","year":"2015","unstructured":"Musiek, E. S. & Holtzman, D. M. Three dimensions of the amyloid hypothesis: time, space and \u2018wingmen\u2019. Nat. Neurosci. 18, 800\u2013806 (2015).","journal-title":"Nat. Neurosci."},{"key":"1189_CR14","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1038\/s41583-021-00531-y","volume":"22","author":"P Padmanabhan","year":"2021","unstructured":"Padmanabhan, P., Kneynsberg, A. & G\u00f6tz, J. Super-resolution microscopy: a closer look at synaptic dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 22, 723\u2013740 (2021).","journal-title":"Nat. Rev. Neurosci."},{"key":"1189_CR15","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/nn.2583","volume":"13","author":"JJ Palop","year":"2010","unstructured":"Palop, J. J. & Mucke, L. Amyloid-\u03b2-induced neuronal dysfunction in Alzheimer\u2019s disease: from synapses toward neural networks. Nat. Neurosci. 13, 812\u2013818 (2010).","journal-title":"Nat. Neurosci."},{"key":"1189_CR16","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/nchembio.2067","volume":"12","author":"B Morgan","year":"2016","unstructured":"Morgan, B. et al. Real-time monitoring of basal H2O2 levels with peroxiredoxin-based probes. Nat. Chem. Biol. 12, 437\u2013443 (2016).","journal-title":"Nat. Chem. Biol."},{"key":"1189_CR17","doi-asserted-by":"publisher","first-page":"109620","DOI":"10.1016\/j.celrep.2021.109620","volume":"36","author":"E de Tredern","year":"2021","unstructured":"de Tredern, E. et al. Glial glucose fuels the neuronal pentose phosphate pathway for long-term memory. Cell Rep. 36, 109620 (2021).","journal-title":"Cell Rep."},{"key":"1189_CR18","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s42255-022-00528-6","volume":"4","author":"B Silva","year":"2022","unstructured":"Silva, B. et al. Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation. Nat. Metab. 4, 213\u2013224 (2022).","journal-title":"Nat. Metab."},{"key":"1189_CR19","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1038\/s42255-023-00910-y","volume":"5","author":"Y Rabah","year":"2023","unstructured":"Rabah, Y. et al. Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila. Nat. Metab. 5, 2002\u20132019 (2023).","journal-title":"Nat. Metab."},{"key":"1189_CR20","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1126\/science.1064200","volume":"294","author":"A Pascual","year":"2001","unstructured":"Pascual, A. & Pr\u00e9at, T. Localization of long-term memory within the Drosophila mushroom body. Science 294, 1115\u20131117 (2001).","journal-title":"Science"},{"key":"1189_CR21","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/0092-8674(94)90398-0","volume":"79","author":"T Tully","year":"1994","unstructured":"Tully, T., Preat, T., Boynton, S. C. & Del Vecchio, M. Genetic dissection of consolidated memory in Drosophila. Cell 79, 35\u201347 (1994).","journal-title":"Cell"},{"key":"1189_CR22","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1186\/1471-2148-7-109","volume":"7","author":"T Kawahara","year":"2007","unstructured":"Kawahara, T., Quinn, M. T. & Lambeth, J. D. Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox\/Duox) family of enzymes. BMC Evol. Biol. 7, 109 (2007).","journal-title":"BMC Evol. Biol."},{"key":"1189_CR23","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.freeradbiomed.2007.03.006","volume":"43","author":"DR Ritsick","year":"2007","unstructured":"Ritsick, D. R., Edens, W. A., Finnerty, V. & Lambeth, J. D. Nox regulation of smooth muscle contraction. Free Radic. Biol. Med. 43, 31\u201338 (2007).","journal-title":"Free Radic. Biol. Med."},{"key":"1189_CR24","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.39196","volume":"7","author":"YF Widmer","year":"2018","unstructured":"Widmer, Y. F. et al. Multiple neurons encode CrebB dependent appetitive long-term memory in the mushroom body circuit. eLife 7, e39196 (2018).","journal-title":"eLife"},{"key":"1189_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13471","volume":"7","author":"Y Hirano","year":"2016","unstructured":"Hirano, Y. et al. Shifting transcriptional machinery is required for long-term memory maintenance and modification in Drosophila mushroom bodies. Nat. Commun. 7, 13471 (2016).","journal-title":"Nat. Commun."},{"key":"1189_CR26","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1111\/brv.12140","volume":"90","author":"A Stincone","year":"2015","unstructured":"Stincone, A. et al. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol. Rev. Camb. Philos. Soc. 90, 927\u2013963 (2015).","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"1189_CR27","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1016\/j.neuron.2016.02.015","volume":"89","author":"O Barnstedt","year":"2016","unstructured":"Barnstedt, O. et al. Memory-relevant mushroom body output synapses are cholinergic. Neuron 89, 1237\u20131247 (2016).","journal-title":"Neuron"},{"key":"1189_CR28","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1523\/JNEUROSCI.13-02-00596.1993","volume":"13","author":"P S\u00e9gu\u00e9la","year":"1993","unstructured":"S\u00e9gu\u00e9la, P., Wadiche, J., Dineley-Miller, K., Dani, J. A. & Patrick, J. W. Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J. Neurosci. 13, 596\u2013604 (1993).","journal-title":"J. Neurosci."},{"key":"1189_CR29","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.expneurol.2004.12.015","volume":"192","author":"W-F Yu","year":"2005","unstructured":"Yu, W.-F., Guan, Z.-Z., Bogdanovic, N. & Nordberg, A. High selective expression of \u03b17 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer\u2019s disease and patients carrying Swedish APP 670\/671 mutation: a possible association with neuritic plaques. Exp. Neurol. 192, 215\u2013225 (2005).","journal-title":"Exp. Neurol."},{"key":"1189_CR30","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1038\/s41593-021-00949-8","volume":"24","author":"K Zhang","year":"2021","unstructured":"Zhang, K. et al. Fear learning induces \u03b17-nicotinic acetylcholine receptor-mediated astrocytic responsiveness that is required for memory persistence. Nat. Neurosci. 24, 1686\u20131698 (2021).","journal-title":"Nat. Neurosci."},{"key":"1189_CR31","doi-asserted-by":"publisher","first-page":"R453","DOI":"10.1016\/j.cub.2014.03.034","volume":"24","author":"M Schieber","year":"2014","unstructured":"Schieber, M. & Chandel, N. S. ROS function in redox signaling and oxidative stress. Curr. Biol. 24, R453\u2013R462 (2014).","journal-title":"Curr. Biol."},{"key":"1189_CR32","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1083\/jcb.201708007","volume":"217","author":"Y Wang","year":"2018","unstructured":"Wang, Y., Branicky, R., No\u00eb, A. & Hekimi, S. Superoxide dismutases: dual roles in controlling ROS damage and regulating ROS signaling. J. Cell Biol. 217, 1915\u20131928 (2018).","journal-title":"J. Cell Biol."},{"key":"1189_CR33","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1016\/j.cell.2018.05.057","volume":"174","author":"K Davie","year":"2018","unstructured":"Davie, K. et al. A single-cell transcriptome atlas of the aging Drosophila brain. Cell 174, 982\u2013998.e20 (2018).","journal-title":"Cell"},{"key":"1189_CR34","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.tins.2009.05.001","volume":"32","author":"G Perea","year":"2009","unstructured":"Perea, G., Navarrete, M. & Araque, A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 32, 421\u2013431 (2009).","journal-title":"Trends Neurosci."},{"key":"1189_CR35","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1002\/glia.23115","volume":"65","author":"MC Kremer","year":"2017","unstructured":"Kremer, M. C., Jung, C., Batelli, S., Rubin, G. M. & Gaul, U. The glia of the adult Drosophila nervous system. Glia 65, 606\u2013638 (2017).","journal-title":"Glia"},{"key":"1189_CR36","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1016\/j.neuron.2006.10.030","volume":"52","author":"D Yu","year":"2006","unstructured":"Yu, D., Akalal, D.-B. G. & Davis, R. L. Drosophila \u03b1\/\u03b2mushroom body neurons form a branch-specific, long-term cellular memory trace after spaced olfactory conditioning. Neuron 52, 845\u2013855 (2006).","journal-title":"Neuron"},{"key":"1189_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15510","volume":"8","author":"P-Y Pla\u00e7ais","year":"2017","unstructured":"Pla\u00e7ais, P.-Y. et al. Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory. Nat. Commun. 8, 15510 (2017).","journal-title":"Nat. Commun."},{"key":"1189_CR38","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1016\/j.bbagen.2013.09.017","volume":"1840","author":"GP Bienert","year":"2014","unstructured":"Bienert, G. P. & Chaumont, F. Aquaporin-facilitated transmembrane diffusion of hydrogen peroxide. Biochim. Biophys. Acta 1840, 1596\u20131604 (2014).","journal-title":"Biochim. Biophys. Acta"},{"key":"1189_CR39","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1089\/ars.2017.7162","volume":"28","author":"S St\u00f6cker","year":"2018","unstructured":"St\u00f6cker, S., Van Laer, K., Mijuskovic, A. & Dick, T. P. The conundrum of hydrogen peroxide signaling and the emerging role of peroxiredoxins as redox relay hubs. Antioxid. Redox Signal. 28, 558\u2013573 (2018).","journal-title":"Antioxid. Redox Signal."},{"key":"1189_CR40","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1146\/annurev-biochem-060815-014431","volume":"86","author":"SG Rhee","year":"2017","unstructured":"Rhee, S. G. & Kil, I. S. Multiple functions and regulation of mammalian peroxiredoxins. Annu. Rev. Biochem. 86, 749\u2013775 (2017).","journal-title":"Annu. Rev. Biochem."},{"key":"1189_CR41","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1016\/j.celrep.2015.04.044","volume":"11","author":"E Bouzaiane","year":"2015","unstructured":"Bouzaiane, E., Trannoy, S., Scheunemann, L., Pla\u00e7ais, P.-Y. & Preat, T. Two independent mushroom body output circuits retrieve the six discrete components of Drosophila aversive memory. Cell Rep. 11, 1280\u20131292 (2015).","journal-title":"Cell Rep."},{"key":"1189_CR42","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.neuint.2015.07.006","volume":"90","author":"N D\u2019Ambrosi","year":"2015","unstructured":"D\u2019Ambrosi, N. & Rossi, L. Copper at synapse: release, binding and modulation of neurotransmission. Neurochem. Int. 90, 36\u201345 (2015).","journal-title":"Neurochem. Int."},{"key":"1189_CR43","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3389\/fnmol.2017.00021","volume":"10","author":"K Wild","year":"2017","unstructured":"Wild, K., August, A., Pietrzik, C. U. & Kins, S. Structure and synaptic function of metal binding to the amyloid precursor protein and its proteolytic fragments. Front. Mol. Neurosci. 10, 21 (2017).","journal-title":"Front. Mol. Neurosci."},{"key":"1189_CR44","doi-asserted-by":"publisher","first-page":"4165","DOI":"10.1021\/acs.biochem.8b00572","volume":"57","author":"TR Young","year":"2018","unstructured":"Young, T. R., Pukala, T. L., Cappai, R., Wedd, A. G. & Xiao, Z. The human amyloid precursor protein binds copper ions dominated by a picomolar-affinity site in the helix-rich E2 domain. Biochemistry 57, 4165\u20134176 (2018).","journal-title":"Biochemistry"},{"key":"1189_CR45","doi-asserted-by":"publisher","first-page":"13913","DOI":"10.1074\/jbc.M409179200","volume":"280","author":"R Cappai","year":"2005","unstructured":"Cappai, R. et al. The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu\/Zn-nitric oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. J. Biol. Chem. 280, 13913\u201313920 (2005).","journal-title":"J. Biol. Chem."},{"key":"1189_CR46","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.jmb.2011.12.057","volume":"416","author":"SO Dahms","year":"2012","unstructured":"Dahms, S. O. et al. Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain. J. Mol. Biol. 416, 438\u2013452 (2012).","journal-title":"J. Mol. Biol."},{"key":"1189_CR47","doi-asserted-by":"publisher","first-page":"6289","DOI":"10.1021\/bi3006169","volume":"51","author":"G Eskici","year":"2012","unstructured":"Eskici, G. & Axelsen, P. H. Copper and oxidative stress in the pathogenesis of Alzheimer\u2019s disease. Biochemistry 51, 6289\u20136311 (2012).","journal-title":"Biochemistry"},{"key":"1189_CR48","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1523\/JNEUROSCI.2896-10.2011","volume":"31","author":"V Goguel","year":"2011","unstructured":"Goguel, V. et al. Drosophila amyloid precursor protein-like is required for long-term memory. J. Neurosci. 31, 1032\u20131037 (2011).","journal-title":"J. Neurosci."},{"key":"1189_CR49","doi-asserted-by":"publisher","first-page":"2944","DOI":"10.1038\/sj.emboj.7600757","volume":"24","author":"M Leyssen","year":"2005","unstructured":"Leyssen, M. et al. Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. EMBO J. 24, 2944\u20132955 (2005).","journal-title":"EMBO J."},{"key":"1189_CR50","doi-asserted-by":"publisher","first-page":"a006288","DOI":"10.1101\/cshperspect.a006288","volume":"2","author":"UC M\u00fcller","year":"2012","unstructured":"M\u00fcller, U. C. & Zheng, H. Physiological functions of APP family proteins. Cold Spring Harb. Perspect. Med. 2, a006288 (2012).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"1189_CR51","first-page":"161","volume":"9","author":"S Ludewig","year":"2016","unstructured":"Ludewig, S. & Korte, M. Novel insights into the physiological function of the APP (gene) family and its proteolytic fragments in synaptic plasticity. Front. Mol. Neurosci. 9, 161 (2016).","journal-title":"Front. Mol. Neurosci."},{"key":"1189_CR52","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1523\/JNEUROSCI.2093-14.2015","volume":"35","author":"I Bourdet","year":"2015","unstructured":"Bourdet, I., Preat, T. & Goguel, V. The full-length form of the Drosophila amyloid precursor protein is involved in memory formation. J. Neurosci. 35, 1043\u20131051 (2015).","journal-title":"J. Neurosci."},{"key":"1189_CR53","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1046\/j.1471-4159.2000.0751155.x","volume":"75","author":"HY Wang","year":"2000","unstructured":"Wang, H. Y., Lee, D. H., Davis, C. B. & Shank, R. P. Amyloid peptide A\u03b2(1-42) binds selectively and with picomolar affinity to \u03b17 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155\u20131161 (2000).","journal-title":"J. Neurochem."},{"key":"1189_CR54","doi-asserted-by":"publisher","first-page":"25056","DOI":"10.1074\/jbc.M200066200","volume":"277","author":"KT Dineley","year":"2002","unstructured":"Dineley, K. T., Bell, K. A., Bui, D. & Sweatt, J. D. \u03b2-Amyloid peptide activates \u03b17 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J. Biol. Chem. 277, 25056\u201325061 (2002).","journal-title":"J. Biol. Chem."},{"key":"1189_CR55","doi-asserted-by":"publisher","first-page":"4734","DOI":"10.1073\/pnas.081553598","volume":"98","author":"Q Liu","year":"2001","unstructured":"Liu, Q., Kawai, H. & Berg, D. K. \u03b2-Amyloid peptide blocks the response of \u03b17-containing nicotinic receptors on hippocampal neurons. Proc. Natl Acad. Sci. USA 98, 4734\u20134739 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1189_CR56","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/cr.2011.116","volume":"22","author":"Q Guo","year":"2012","unstructured":"Guo, Q., Wang, Z., Li, H., Wiese, M. & Zheng, H. APP physiological and pathophysiological functions: insights from animal models. Cell Res. 22, 78\u201389 (2012).","journal-title":"Cell Res."},{"key":"1189_CR57","doi-asserted-by":"publisher","first-page":"6623","DOI":"10.1073\/pnas.0400895101","volume":"101","author":"K Iijima","year":"2004","unstructured":"Iijima, K. et al. Dissecting the pathological effects of human A\u03b240 and A\u03b242 in Drosophila: a potential model for Alzheimer\u2019s disease. Proc. Natl Acad. Sci. USA 101, 6623\u20136628 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1189_CR58","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.mcn.2004.03.001","volume":"26","author":"A Finelli","year":"2004","unstructured":"Finelli, A., Kelkar, A., Song, H.-J., Yang, H. & Konsolaki, M. A model for studying Alzheimer\u2019s A\u03b242-induced toxicity in Drosophila melanogaster. Mol. Cell. Neurosci. 26, 365\u2013375 (2004).","journal-title":"Mol. Cell. Neurosci."},{"key":"1189_CR59","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.neurobiolaging.2021.07.014","volume":"107","author":"A Ionescu-Tucker","year":"2021","unstructured":"Ionescu-Tucker, A. & Cotman, C. W. Emerging roles of oxidative stress in brain aging and Alzheimer\u2019s disease. Neurobiol. Aging 107, 86\u201395 (2021).","journal-title":"Neurobiol. Aging"},{"key":"1189_CR60","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1097\/WAD.0b013e31815721c3","volume":"21","author":"Q Shi","year":"2007","unstructured":"Shi, Q. & Gibson, G. E. Oxidative stress and transcriptional regulation in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 21, 276\u2013291 (2007).","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"1189_CR61","doi-asserted-by":"publisher","first-page":"3394","DOI":"10.1523\/JNEUROSCI.23-08-03394.2003","volume":"23","author":"AY Shih","year":"2003","unstructured":"Shih, A. Y. et al. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci. 23, 3394\u20133406 (2003).","journal-title":"J. Neurosci."},{"key":"1189_CR62","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1038\/cdd.2015.49","volume":"22","author":"D Jimenez-Blasco","year":"2015","unstructured":"Jimenez-Blasco, D., Santofimia-Casta\u00f1o, P., Gonzalez, A., Almeida, A. & Bola\u00f1os, J. P. Astrocyte NMDA receptors\u2019 activity sustains neuronal survival through a Cdk5\u2013Nrf2 pathway. Cell Death Differ. 22, 1877\u20131889 (2015).","journal-title":"Cell Death Differ."},{"key":"1189_CR63","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.cmet.2017.08.024","volume":"26","author":"L Liu","year":"2017","unstructured":"Liu, L., MacKenzie, K. R., Putluri, N., Maleti\u0107-Savati\u0107, M. & Bellen, H. J. The glia-neuron lactate shuttle and elevated ROS promote lipid synthesis in neurons and lipid droplet accumulation in glia via APOE\/D. Cell Metab. 26, 719\u2013737.e6 (2017).","journal-title":"Cell Metab."},{"key":"1189_CR64","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1089\/ars.2018.7697","volume":"31","author":"NM Mishina","year":"2019","unstructured":"Mishina, N. M. et al. Which antioxidant system shapes intracellular H2O2 gradients? Antioxid. Redox Signal. 31, 664\u2013670 (2019).","journal-title":"Antioxid. Redox Signal."},{"key":"1189_CR65","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1152\/jn.01283.2007","volume":"99","author":"GC Turner","year":"2008","unstructured":"Turner, G. C., Bazhenov, M. & Laurent, G. Olfactory representations by Drosophila mushroom body neurons. J. Neurophysiol. 99, 734\u2013746 (2008).","journal-title":"J. Neurophysiol."},{"key":"1189_CR66","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1098\/rstb.2002.1224","volume":"358","author":"B Bozon","year":"2003","unstructured":"Bozon, B. et al. MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 805\u2013814 (2003).","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"1189_CR67","doi-asserted-by":"publisher","first-page":"361","DOI":"10.3389\/fnmol.2018.00361","volume":"11","author":"JH Medina","year":"2018","unstructured":"Medina, J. H. & Viola, H. ERK1\/2: a key cellular component for the formation, retrieval, reconsolidation and persistence of memory. Front. Mol. Neurosci. 11, 361 (2018).","journal-title":"Front. Mol. Neurosci."},{"key":"1189_CR68","doi-asserted-by":"publisher","first-page":"4138","DOI":"10.1074\/jbc.271.8.4138","volume":"271","author":"KZ Guyton","year":"1996","unstructured":"Guyton, K. Z., Liu, Y., Gorospe, M., Xu, Q. & Holbrook, N. J. Activation of mitogen-activated protein kinase by H2O2. J. Biol. Chem. 271, 4138\u20134142 (1996).","journal-title":"J. Biol. Chem."},{"key":"1189_CR69","doi-asserted-by":"publisher","first-page":"101340","DOI":"10.1016\/j.redox.2019.101340","volume":"28","author":"AG Barata","year":"2020","unstructured":"Barata, A. G. & Dick, T. P. A role for peroxiredoxins in H2O2- and MEKK-dependent activation of the p38 signaling pathway. Redox Biol. 28, 101340 (2020).","journal-title":"Redox Biol."},{"key":"1189_CR70","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1002\/jnr.23143","volume":"91","author":"ED Gaier","year":"2013","unstructured":"Gaier, E. D., Eipper, B. A. & Mains, R. E. Copper signaling in the mammalian nervous system: synaptic effects. J. Neurosci. Res. 91, 2\u201319 (2013).","journal-title":"J. Neurosci. Res."},{"key":"1189_CR71","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.neuron.2015.11.013","volume":"89","author":"Y Zhang","year":"2016","unstructured":"Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37\u201353 (2016).","journal-title":"Neuron"},{"key":"1189_CR72","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/jnc.12358","volume":"127","author":"M La\u00dfek","year":"2013","unstructured":"La\u00dfek, M. et al. Amyloid precursor proteins are constituents of the presynaptic active zone. J. Neurochem. 127, 48\u201356 (2013).","journal-title":"J. Neurochem."},{"key":"1189_CR73","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fnmol.2017.00087","volume":"10","author":"S Gu\u00e9nette","year":"2017","unstructured":"Gu\u00e9nette, S., Strecker, P. & Kins, S. APP protein family signaling at the synapse: insights from intracellular APP-binding proteins. Front. Mol. Neurosci. 10, 87 (2017).","journal-title":"Front. Mol. Neurosci."},{"key":"1189_CR74","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.neuron.2020.08.011","volume":"108","author":"SH Lee","year":"2020","unstructured":"Lee, S. H. et al. APP family regulates neuronal excitability and synaptic plasticity but not neuronal survival. Neuron 108, 676\u2013690.e8 (2020).","journal-title":"Neuron"},{"key":"1189_CR75","doi-asserted-by":"publisher","first-page":"1138577","DOI":"10.3389\/fnsyn.2023.1138577","volume":"15","author":"J Goenaga","year":"2023","unstructured":"Goenaga, J., Araque, A., Kofuji, P. & Herrera Moro Chao, D. Calcium signaling in astrocytes and gliotransmitter release. Front. Synaptic Neurosci. 15, 1138577 (2023).","journal-title":"Front. Synaptic Neurosci."},{"key":"1189_CR76","doi-asserted-by":"publisher","first-page":"RC120","DOI":"10.1523\/JNEUROSCI.21-01-j0003.2001","volume":"21","author":"DL Pettit","year":"2001","unstructured":"Pettit, D. L., Shao, Z. & Yakel, J. L. \u03b2-Amyloid(1-42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J. Neurosci. 21, RC120 (2001).","journal-title":"J. Neurosci."},{"key":"1189_CR77","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1016\/j.neuron.2016.09.006","volume":"91","author":"EC Ballinger","year":"2016","unstructured":"Ballinger, E. C., Ananth, M., Talmage, D. A. & Role, L. W. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron 91, 1199\u20131218 (2016).","journal-title":"Neuron"},{"key":"1189_CR78","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13249","volume":"7","author":"TW Schmitz","year":"2016","unstructured":"Schmitz, T. W., Nathan Spreng, R. & Alzheimer\u2019s Disease Neuroimaging Initiative. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer\u2019s pathology. Nat. Commun. 7, 13249 (2016).","journal-title":"Nat. Commun."},{"key":"1189_CR79","doi-asserted-by":"publisher","first-page":"e0168812","DOI":"10.1371\/journal.pone.0168812","volume":"11","author":"M Zhang","year":"2016","unstructured":"Zhang, M. et al. Drug repositioning for Alzheimer\u2019s disease based on systematic \u2018omics\u2019 data mining. PLoS ONE 11, e0168812 (2016).","journal-title":"PLoS ONE"},{"key":"1189_CR80","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/s41583-023-00677-x","volume":"24","author":"MR Ananth","year":"2023","unstructured":"Ananth, M. R., Rajebhosale, P., Kim, R., Talmage, D. A. & Role, L. W. Basal forebrain cholinergic signalling: development, connectivity and roles in cognition. Nat. Rev. Neurosci. 24, 233\u2013251 (2023).","journal-title":"Nat. Rev. Neurosci."},{"key":"1189_CR81","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1126\/science.1089035","volume":"302","author":"SE McGuire","year":"2003","unstructured":"McGuire, S. E., Le, P. T., Osborn, A. J., Matsumoto, K. & Davis, R. L. Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302, 1765\u20131768 (2003).","journal-title":"Science"},{"key":"1189_CR82","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1007\/BF01350033","volume":"157","author":"T Tully","year":"1985","unstructured":"Tully, T. & Quinn, W. G. Classical conditioning and retention in normal and mutant Drosophila melanogaster. J. Comp. Physiol. [A] 157, 263\u2013277 (1985).","journal-title":"J. Comp. Physiol. [A]"},{"key":"1189_CR83","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1007\/s10534-011-9463-0","volume":"24","author":"L Bonilla-Ramirez","year":"2011","unstructured":"Bonilla-Ramirez, L., Jimenez-Del-Rio, M. & Velez-Pardo, C. Acute and chronic metal exposure impairs locomotion activity in Drosophila melanogaster: a model to study Parkinsonism. Biometals 24, 1045\u20131057 (2011).","journal-title":"Biometals"},{"key":"1189_CR84","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1534\/genetics.110.119917","volume":"186","author":"BD Pfeiffer","year":"2010","unstructured":"Pfeiffer, B. D. et al. Refinement of tools for targeted gene expression in Drosophila. Genetics 186, 735\u2013755 (2010).","journal-title":"Genetics"},{"key":"1189_CR85","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1093\/genetics\/iyad211","volume":"227","author":"A \u00d6zt\u00fcrk-\u00c7olak","year":"2024","unstructured":"\u00d6zt\u00fcrk-\u00c7olak, A. et al. FlyBase: updates to the Drosophila genes and genomes database. Genetics 227, 211 (2024).","journal-title":"Genetics"},{"key":"1189_CR86","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1126\/science.1134426","volume":"314","author":"KJT Venken","year":"2006","unstructured":"Venken, K. J. T., He, Y., Hoskins, R. A. & Bellen, H. J. P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science 314, 1747\u20131751 (2006).","journal-title":"Science"}],"container-title":["Nature Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42255-024-01189-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42255-024-01189-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42255-024-01189-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T23:02:59Z","timestamp":1740524579000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42255-024-01189-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,24]]},"references-count":86,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["1189"],"URL":"https:\/\/doi.org\/10.1038\/s42255-024-01189-3","relation":{},"ISSN":["2522-5812"],"issn-type":[{"value":"2522-5812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,24]]},"assertion":[{"value":"15 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 January 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}