{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:04:48Z","timestamp":1792677888798,"version":"4.5.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T00:00:00Z","timestamp":1663200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31972907"],"award-info":[{"award-number":["31972907"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["61431012"],"award-info":[{"award-number":["61431012"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U1913216"],"award-info":[{"award-number":["U1913216"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The main manifestation of Alzheimer\u2019s disease (AD) in patients and animal models is impaired memory function, characterized by amyloid-beta (A\u03b2) deposition and impairment of gamma oscillations that play an important role in perception and cognitive function. The therapeutic effect of gamma band stimulation in AD mouse models has been reported recently. Transcranial alternating current stimulation (tACS) is an emerging non-invasive intervention method, but at present, researchers have not completely understood the intervention effect of tACS. Thus, the intervention mechanism of tACS has not been fully elucidated, and the course of treatment in clinical selection also lacks theoretical support. Based on this issue, we investigated the effect of gamma frequency (40 Hz) tACS at different durations in a mouse model of AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      We placed stimulating electrodes on the skull surface of APP\/PS1 and wild-type control mice (\n                      <jats:italic>n<\/jats:italic>\n                      = 30 and\n                      <jats:italic>n<\/jats:italic>\n                      = 5, respectively). Among them, 20 APP\/PS1 mice were divided into 4 groups to receive 20 min 40 Hz tACS every day for 1\u20134 weeks. The other 10 APP\/PS1 mice were equally divided into two groups to receive sham treatment and no treatment. No intervention was performed in the wild-type control mice. The short-term memory function of the mice was examined by the Y maze. A\u03b2 levels and microglia in the hippocampus were measured by immunofluorescence. Spontaneous electroencephalogram gamma power was calculated by the average period method, and brain connectivity was examined by cross-frequency coupling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that the long-term treatment groups (21 and 28 days) had decreased hippocampal A\u03b2 levels, increased electroencephalogram spontaneous gamma power, and ultimately improved short-term memory function. The treatment effect of the short-term treatment group (7 days) was not significant. Moreover, the treatment effect of the 14-day treatment group was weaker than that of the 21-day treatment group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These results suggest that long-term gamma-frequency tACS is more effective in treating AD by reducing A\u03b2 load and improving gamma oscillation than short-term gamma-frequency tACS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2022.980636","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T05:59:47Z","timestamp":1663221587000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Long-term gamma transcranial alternating current stimulation improves the memory function of mice with Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Linyan","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chujie","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/nature.2016.21045","article-title":"Leading Alzheimer\u2019s theory survives drug failure.","volume":"540","author":"Abbott","year":"2016","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2665","DOI":"10.1523\/JNEUROSCI.23-07-02665.2003","article-title":"cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation.","volume":"23","author":"Bamberger","year":"2003","journal-title":"J. Neurosci."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4122-11.2012","article-title":"Cross-frequency phase\u2013phase coupling between theta and gamma oscillations in the hippocampus.","volume":"32","author":"Belluscio","year":"2012","journal-title":"J. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1038\/nn.2801","article-title":"Neuronal activity regulates the regional vulnerability to amyloid-b deposition.","volume":"14","author":"Bero","year":"2011","journal-title":"Nat. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.609073","article-title":"Modulation of \u03b2-amyloid fibril formation in Alzheimer\u2019s disease by microglia and infection.","volume":"13","author":"Brown","year":"2013","journal-title":"Front. Mol. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/mp.2011.31","article-title":"A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior.","volume":"17","author":"Carl\u00e9n","year":"2012","journal-title":"Mol. Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.neuron.2014.11.020","article-title":"Immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior.","volume":"85","author":"Chakrabarty","year":"2015","journal-title":"Neuron"},{"key":"B8","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.neuron.2005.10.028","article-title":"Synaptic activity regulates interstitialfluid amyloid-beta levels in vivo.","volume":"48","author":"Cirrito","year":"2005","journal-title":"Neuron"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00067","article-title":"The Effects of 10 Hz Transcranial Alternating Current Stimulation on Audiovisual Task Switching.","volume":"12","author":"Clayton","year":"2018","journal-title":"Front. Neurosci."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12050","article-title":"Alzheimer\u2019s disease drug development pipeline: 2020.","volume":"6","author":"Cummings","year":"2020","journal-title":"Alzheimers Dement."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1016\/j.brs.2020.05.013","article-title":"LTP-like cortical plasticity predicts conversion to dementia in patients with memory impairment.","volume":"13","author":"Di Lorenzo","year":"2020","journal-title":"Brain Stimul."},{"key":"B12","doi-asserted-by":"publisher","first-page":"983","DOI":"10.3233\/JAD-180503","article-title":"Impaired Spike Timing Dependent Cortico-Cortical Plasticity in Alzheimer\u2019s Disease Patients.","volume":"66","author":"Di Lorenzo","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"158","DOI":"10.4103\/1673-5374.232486","article-title":"Association between Alzheimer\u2019s disease pathogenesis and early demyelination and oligodendrocyte dysfunction.","volume":"13","author":"Dong","year":"2018","journal-title":"Neural Regen. Res."},{"key":"B14","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1152\/physrev.00042.2016","article-title":"Physiology of Astroglia.","volume":"98","author":"Erkhratsky","year":"2018","journal-title":"Physiol. Rev."},{"key":"B15","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/j.neuron.2016.04.009","article-title":"Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples.","volume":"90","author":"Gillespie","year":"2016","journal-title":"Neuron"},{"key":"B16","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.neuron.2013.04.014","article-title":"Alzheimer\u2019s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta.","volume":"78","author":"Griciuc","year":"2013","journal-title":"Neuron"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1109\/TBME.2020.3022332","article-title":"Glial Modulation of Electrical Rhythms in a Neuroglial Network Model of Epilepsy.","volume":"68","author":"Grigorovsky","year":"2018","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"B18","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/ni.3102","article-title":"Innate immunity in Alzheimer\u2019s disease.","volume":"16","author":"Heneka","year":"2015","journal-title":"Nat. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.bandc.2015.11.002","article-title":"The effect of \u03b3-tacs on working memory performance in healthy controls.","volume":"101","author":"Hoy","year":"2015","journal-title":"Brain Cogn."},{"key":"B20","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/nature20587","article-title":"Gamma frequency entrainment attenuates amyloid load and modifies microglia.","volume":"540","author":"Iaccarino","year":"2016","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1038\/nm.3639","article-title":"GABA from reactive astrocytes impairs memory in mouse models of Alzheimer\u2019s disease.","volume":"20","author":"Jo","year":"2014","journal-title":"Nat. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/0304-3940(93)90341-H","article-title":"Basket-like interneurones in layer II of the entorhinal cortex exhibit a powerful NMDA-mediated synaptic excitation.","volume":"149","author":"Jones","year":"1993","journal-title":"Neurosci. Lett."},{"key":"B23","doi-asserted-by":"publisher","first-page":"9389","DOI":"10.1523\/JNEUROSCI.1390-17.2017","article-title":"Simultaneously excitatory and inhibitory effects of transcranial alternating current stimulation revealed using selective pulse-train stimulation in the rat motor cortex.","volume":"37","author":"Khatoun","year":"2017","journal-title":"J. Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.neurobiolaging.2004.03.008","article-title":"Decreased EEG synchronization in Alzheimer\u2019s disease and mild cognitive impairment.","volume":"26","author":"Koenig","year":"2005","journal-title":"Neurobiol. Aging"},{"key":"B25","doi-asserted-by":"publisher","first-page":"9918","DOI":"10.1523\/JNEUROSCI.1378-09.2009","article-title":"Robust Conjunctive Item\u2013Place Coding by Hippocampal Neurons Parallels Learning What Happens Where.","volume":"29","author":"Komorowski","year":"2009","journal-title":"J. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/ene.13439","article-title":"Alzheimer\u2019s disease.","volume":"25","author":"Lane","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"B27","first-page":"425","article-title":"Brain-derived neurotrophic factor prevents against amyloid beta protein-induced impairment of hippocampal in vivo long-term potentiation in rats.","volume":"28","author":"Li","year":"2012","journal-title":"Zhongguo Ying Yong Sheng Li Xue Za Zhi"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-020-00656-9","article-title":"Intracranial alternating current stimulation facilitates neurogenesis in a mouse model of Alzheimer\u2019s disease.","volume":"12","author":"Liu","year":"2020","journal-title":"Alzheimers Res. Ther."},{"key":"B29","first-page":"225","article-title":"Effects of the pathology of senile plaques in cerebral cortex on the learning and memory abilities of the APP\/PS1 transgenic mice.","volume":"23","author":"Liu","year":"2007","journal-title":"Chin. J. Neurol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.conb.2018.07.009","article-title":"Gamma oscillations in cognitive disorders.","volume":"52","author":"Mably","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.02.014","article-title":". Multi-sensory Gamma Stimulation Ameliorates Alzheimer\u2019s-Associated Pathology and Improves Cognition.","volume":"177","author":"Martorell","year":"2019","journal-title":"Cell"},{"key":"B32","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1080\/13543784.2017.1323868","article-title":"Why do trials for Alzheimer\u2019s disease drugs keep failing? A discontinued drug perspective for 2010\u20132015.","volume":"26","author":"Mehta","year":"2017","journal-title":"Expert Opin. Investig. Drugs"},{"key":"B33","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1038\/nature06616","article-title":"Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer\u2019s disease.","volume":"451","author":"Meyer-Luehmann","year":"2008","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1016\/j.brs.2021.09.006","article-title":"Predictive models for response to non-invasive brain stimulation in stroke: A critical review of opportunities and pitfalls.","volume":"14","author":"Mjwa","year":"2021","journal-title":"Brain Stimul."},{"key":"B35","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.neuroscience.2018.12.042","article-title":"Functional Connectivity between Hippocampus and Lateral Septum is Affected in Very Young Alzheimer\u2019s Transgenic Mouse Model.","volume":"401","author":"Mondrag\u00f3n-Rodr\u00edguez","year":"2018","journal-title":"Neuroscience"},{"key":"B36","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1038\/s41591-019-0375-9","article-title":"Adult hippocampal neurogenesis is abundant inneurologically healthy subjects and drops sharply in patients with Alzheimer\u2019s disease.","volume":"25","author":"Moreno-Jimenez","year":"2019","journal-title":"Nat. Med."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13581-z","article-title":"Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury.","volume":"7","author":"Morrison","year":"2017","journal-title":"Sci. Rep."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-021-00274-x","article-title":"Effects of transcranial ultrasound stimulation pulsed at 40Hz on A\u03b2 plaques and brain rhythms in 5\u00d7FAD mice.","volume":"10","author":"Park","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2048","DOI":"10.1038\/s41591-021-01568-3","article-title":"Microglial activation and tau propagate jointly across braak stages.","volume":"27","author":"Pascoal","year":"2021","journal-title":"Nat. Med."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.2019","article-title":"\u03b1\u2212tACS over the somatosensory cortex enhances tactile spatial discrimination in healthy subjects with low alpha activity.","volume":"11","author":"Saito","year":"2021","journal-title":"Brain and Behav."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease.","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"B42","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/nature07991","article-title":"Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.","volume":"459","author":"Sohal","year":"2009","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","first-page":"4637","DOI":"10.1073\/pnas.1813562116","article-title":"Priming of microglia with IFN-\u03b3 slows neuronal gamma oscillations in situ.","volume":"116","author":"Ta","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B44","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.brainresbull.2020.11.003","article-title":"Disrupted prefrontal neuronal oscillations and morphology induced by sleep deprivation in young APP\/PS1 transgenic ad mice.","volume":"166","author":"Tabassum","year":"2020","journal-title":"Brain Res. Bull."},{"key":"B45","doi-asserted-by":"publisher","first-page":"20942","DOI":"10.1073\/pnas.0911331106","article-title":"Theta\u2014gamma coupling increases during the learning of item\u2014context associations.","volume":"106","author":"Tort","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B46","doi-asserted-by":"publisher","first-page":"20517","DOI":"10.1073\/pnas.0810524105","article-title":"Dynamic cross-frequency couplings of local field potential oscillations in rat striatum and hippocampus during performance of a T-maze task.","volume":"105","author":"Tort","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2012.09.002","article-title":"Theta-associated high-frequency oscillations (110-160Hz) in the hippocampus and neocortex.","volume":"100","author":"Tort","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3178","article-title":"Alzheimer amyloid-\u03b2 oligomer bound to postsynaptic prion protein activates Fyn to impair neurons.","volume":"15","author":"Um","year":"2012","journal-title":"Nat. Neurosci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1152\/physrev.00042.2016","article-title":"Physiology of astroglia.","volume":"98","author":"Verkhratsky","year":"2018","journal-title":"Physiol. Rev."},{"key":"B50","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.cell.2012.02.046","article-title":"Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model.","volume":"149","author":"Verret","year":"2012","journal-title":"Cell"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/fnsys.2022.827353","article-title":"Entrainment and Spike-Timing Dependent Plasticity-A Review of Proposed Mechanisms of Transcranial Alternating Current Stimulation.","volume":"16","author":"Vogeti","year":"2022","journal-title":"Front. Syst. Neurosci."},{"key":"B52","first-page":"184","article-title":"Dynamic alteration of neprilysin and endothelin-converting enzyme in age-dependent APPswe\/PS1dE9 mouse model of Alzheimer\u2019s disease.","volume":"9","author":"Zhou","year":"2017","journal-title":"Am. J. Transl. Res."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.980636\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T05:59:54Z","timestamp":1663221594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.980636\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,15]]},"references-count":52,"alternative-id":["10.3389\/fnagi.2022.980636"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2022.980636","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,15]]},"article-number":"980636"}}