{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:55:39Z","timestamp":1791557739902,"version":"4.3.4"},"reference-count":60,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T00:00:00Z","timestamp":1743206400000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["AARG\u201021\u2010847542"],"award-info":[{"award-number":["AARG\u201021\u2010847542"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK111436"],"award-info":[{"award-number":["DK111436"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Physical exercise is a primary defense against age\u2010related cognitive decline and Alzheimer's disease (AD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We conducted single\u2010nucleus transcriptomic and chromatin accessibility analyses (snRNA\u2010seq and snATAC\u2010seq) on the hippocampus of mice carrying mutations in the amyloid precursor protein gene (APP\n                      <jats:sup>NL\u2010G\u2010F<\/jats:sup>\n                      ) following prolonged voluntary wheel\u2010running exercise.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Exercise mitigates amyloid\u2010induced changes in transcriptome and chromatin accessibility through cell type\u2013specific regulatory networks converging on growth factor signaling, particularly the epidermal growth factor receptor (EGFR) signaling. The beneficial effects of exercise on neurocognition can be blocked by pharmacological inhibition of EGFR and its downstream PI3K signaling. Exercise leads to elevated levels of heparin\u2010binding EGF (HB\u2010EGF), and intranasal administration of HB\u2010EGF enhances memory function in sedentary APP\n                      <jats:sup>NL\u2010G\u2010F<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings offer a panoramic delineation of cell type\u2013specific hippocampal transcriptional networks activated by exercise and suggest EGFR signaling as a druggable contributor to exercise\u2010induced memory enhancement to combat AD\u2010related cognitive decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            snRNA\u2010seq and snATAC\u2010seq analysis of APP\n                            <jats:sup>NL\u2010G\u2010F<\/jats:sup>\n                            mice after prolonged wheel\u2010running.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Exercise counteracts amyloid\u2010induced transcriptomic and accessibility changes.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Networks converge on the activation of EGFR and insulin signaling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Pharmacological inhibition of EGFR and PI3K blocked cognitive benefits of exercise.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Intranasal HB\u2010EGF administration enhances memory in sedentary APP\n                            <jats:sup>NL\u2010G\u2010F<\/jats:sup>\n                            mice.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70024","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T04:27:08Z","timestamp":1743395228000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Multi\u2010omics delineate growth factor network underlying exercise effects in an Alzheimer's mouse model"],"prefix":"10.1002","volume":"21","author":[{"given":"Xin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaozhong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine Houston Texas USA"},{"name":"Jan and Dan Duncan Neurologic Research Institute Texas Children's Hospital Houston Texas USA"},{"name":"Graduate School of Biomedical Sciences, Program in Quantitative &amp; Computational Biosciences Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guantong","family":"Qi","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurologic Research Institute Texas Children's Hospital Houston Texas USA"},{"name":"Graduate School of Biomedical Sciences, Program in Genetics Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwan","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohao","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine Houston Texas USA"},{"name":"Jan and Dan Duncan Neurologic Research Institute Texas Children's Hospital Houston Texas USA"},{"name":"Graduate School of Biomedical Sciences, Program in Quantitative &amp; Computational Biosciences Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica C.","family":"Ciliberto","sequence":"additional","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"},{"name":"Department of Biochemistry and Molecular Biology School of Basic Medical Sciences, Peking University Health Science Center Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udhaya","family":"Kumar S","sequence":"additional","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyin","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Nephrology Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zheng","sequence":"additional","affiliation":[{"name":"Huffington Center on Aging Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhandong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine Houston Texas USA"},{"name":"Jan and Dan Duncan Neurologic Research Institute Texas Children's Hospital Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine Houston Texas USA"},{"name":"Jan and Dan Duncan Neurologic Research Institute Texas Children's Hospital Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying\u2010Wooi","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine Houston Texas USA"},{"name":"Jan and Dan Duncan Neurologic Research Institute Texas Children's Hospital Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medicine Endocrinology, Diabetes, and Metabolism Baylor College of Medicine Houston Texas USA"},{"name":"Huffington Center on Aging Baylor College of Medicine Houston Texas USA"},{"name":"Department of Molecular and Cellular Biology Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180958"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.156"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tics.2019.01.006"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2017.06.012"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-psych-010814-015249"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3791\/4440"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142301.ns0831s69"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0311-1"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1405648111"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3791\/63669"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.021"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00894-z"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2020.0439"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3697"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2016.07.001"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2011.116"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3333-14.2015"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2018.10.026"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.909989"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-01943-7"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.73600.1"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2017.00035"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2439"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2019.04.008"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.03.013"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.03.018"},{"key":"e_1_2_10_29_1","first-page":"2862","article-title":"Wilms' tumour 1 (WT1) in development, homeostasis and disease","volume":"144","author":"Hastie ND","year":"2017","journal-title":"Dev Camb Engl"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2016.11.011"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2020.611841"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.654031"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2023.01.002"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.038"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04912-w"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1636-8"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.24672"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a020768"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-1647"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-04088-z"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes13040574"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2023.100601"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0196-9781(99)00094-7"},{"key":"e_1_2_10_45_1","article-title":"A single\u2010cell transcriptomic atlas of exercise\u2010induced anti\u2010inflammatory and geroprotective effects across the body","volume":"4","author":"Sun S","year":"2023","journal-title":"Innov Camb Mass"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010023\u201003869\u20109"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tics.2013.08.001"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2022.100993"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10506"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12880"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-020-02139-2"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.120.119909"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.332132"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052719"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3030"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18140-1"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00416-y"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.019414"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77361"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AW119.008146"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-016-0765-2"}],"container-title":["Alzheimer's &amp; Dementia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.70024","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/alz.70024","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.70024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T10:21:38Z","timestamp":1789554098000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/alz.70024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":60,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/alz.70024"],"URL":"https:\/\/doi.org\/10.1002\/alz.70024","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.05.02.592289","asserted-by":"object"}]},"ISSN":["1552-5260","1552-5279"],"issn-type":[{"value":"1552-5260","type":"print"},{"value":"1552-5279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3]]},"assertion":[{"value":"2024-05-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70024"}}