{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:04:03Z","timestamp":1789164243738,"version":"build-2803163510"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073581"],"award-info":[{"award-number":["82073581"]}],"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":["82273673"],"award-info":[{"award-number":["82273673"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004032","name":"Jilin University","doi-asserted-by":"publisher","award":["101832020CX277"],"award-info":[{"award-number":["101832020CX277"]}],"id":[{"id":"10.13039\/501100004032","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004032","name":"Jilin University","doi-asserted-by":"publisher","award":["JJKH20250213BS"],"award-info":[{"award-number":["JJKH20250213BS"]}],"id":[{"id":"10.13039\/501100004032","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004032","name":"Jilin University","doi-asserted-by":"publisher","award":["24GNYZ44"],"award-info":[{"award-number":["24GNYZ44"]}],"id":[{"id":"10.13039\/501100004032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid \u03b2 (A\u03b2) deposition, and synaptic dysfunction. However, the mechanisms underlying neurodegeneration remain poorly understood. In this study, we investigated the therapeutic potential of PBX1, a transcriptional regulator implicated in neurodevelopment and neuroprotection, against AD. PBX1 expression was significantly downregulated in postmortem hippocampal tissues from patients with AD and in the APP\/PS1 mouse model. In\u00a0vitro, PBX1a knockdown reduced neurite complexity and increased apoptosis. PBX1a overexpression reversed these effects and reduced soluble A\u03b2\n                    <jats:sub>1\u201340<\/jats:sub>\n                    and A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    levels. In\u00a0vivo, hippocampal overexpression of PBX1a restored spatial learning and memory, reduced A\u03b2 burden by 41%, and increased neurite length by 1.5\u2010fold. These behavioral and structural improvements were accompanied by reduced levels of hyperphosphorylated Tau and toxic A\u03b2 oligomers. Mechanistically, PBX1 directly activated the transcription of CRTC2\u2014a coactivator of CREB, thereby increasing CRTC2 expression and its nuclear colocalization with phosphorylated CREB. Restoration of the PBX1\u2013CRTC2\u2013CREB axis enhanced neuronal survival and synaptic integrity. Notably, CRTC2 knockdown blocked PBX1\u2010mediated reductions in A\u03b2 deposition, apoptosis, and hyperphosphorylated Tau expression, confirming the role of the PBX1\u2013CRTC2\u2013CREB axis in conferring neuroprotection. Together, our findings indicate that PBX1 is a key modulator of neuronal resilience in AD and that it functions through transcriptional activation of the CRTC2\/CREB pathway. By unraveling a mechanism that links transcriptional regulation to amyloid clearance and cognitive function, this study highlights PBX1 as a promising therapeutic target for AD.\n                  <\/jats:p>","DOI":"10.1111\/acel.70311","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T09:50:20Z","timestamp":1764841820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>PBX1<\/scp>\n                    Improves Cognition and Reduces Amyloid\u2010\u03b2 Pathology in\n                    <scp>APP<\/scp>\n                    \/\n                    <scp>PS1<\/scp>\n                    Mice by Transcriptionally Activating the\n                    <scp>CRTC2<\/scp>\n                    \u2013\n                    <scp>CREB<\/scp>\n                    Pathway"],"prefix":"10.1111","volume":"25","author":[{"given":"Zinan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Toxicology, School of Public Health Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyuan","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Public Health Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rifeng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Public Health Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Histology &amp; Embryology, College of Basic Medical Sciences Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Public Health Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Public Health Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinpeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Public Health Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Public Health Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1000-9434","authenticated-orcid":false,"given":"Jinyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Public Health Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205784"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001323200"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3072"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101619"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2021.09.002"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2008.94"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0757-12.2012"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582\u2010023\u201000883\u20102"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.3.618"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2008.03.004"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2017225118"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00889\u201009"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128033"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2017.00009"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022112453"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyaa039"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010019\u20101382\u2010y"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010021\u201000999\u2010y"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101577"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4849-06.2007"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495\u2010023\u201001848\u2010y"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2009.177"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10616\u2010021\u201000518\u20108"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12445"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.103003"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.04869.x"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.289843"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010016\u20100183\u20100"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010021\u201000894\u2010z"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.778822"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5288\u201013.2014"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.186841"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1419\u201012.2012"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/1749\u20108104\u20107\u201024"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311\u2010014\u20100327\u20105"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201593725"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.172504199"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010023\u201003683\u20103"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.03.011"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u2010220264"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064\u2010018\u20102494\u2010y"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000001880"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41368\u2010024\u201000300\u20104"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.08.012"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2021.113812"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13055"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.030"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14044"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2019.09.006"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001484\u20107"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155671"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1094"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax1798"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70311","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70311","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70311","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T11:56:27Z","timestamp":1774353387000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1111\/acel.70311"],"URL":"https:\/\/doi.org\/10.1111\/acel.70311","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,4]]},"assertion":[{"value":"2025-07-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70311"}}