{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T13:20:55Z","timestamp":1780320055412,"version":"3.54.1"},"reference-count":46,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000},"content-version":"vor","delay-in-days":35,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["MDM\u20102017\u20100729"],"award-info":[{"award-number":["MDM\u20102017\u20100729"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2020\u2010119236RB\u2010I00"],"award-info":[{"award-number":["PID2020\u2010119236RB\u2010I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["SAF2017\u201088812\u2010R"],"award-info":[{"award-number":["SAF2017\u201088812\u2010R"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["MJFF\u2010000858"],"award-info":[{"award-number":["MJFF\u2010000858"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003030","name":"Ag\u00e8ncia de Gesti\u00f3 d'Ajuts Universitaris i de Recerca","doi-asserted-by":"publisher","award":["FI\u2010B\u201000378"],"award-info":[{"award-number":["FI\u2010B\u201000378"]}],"id":[{"id":"10.13039\/501100003030","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008054","name":"Fundaci\u00f3n Ram\u00f3n Areces","doi-asserted-by":"publisher","award":["CIVP21A7024"],"award-info":[{"award-number":["CIVP21A7024"]}],"id":[{"id":"10.13039\/100008054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["FPU21\/02928"],"award-info":[{"award-number":["FPU21\/02928"]}],"id":[{"id":"10.13039\/501100004837","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":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>Alzheimer's disease (AD) pathogenesis involves astrocytic responses to extracellular amyloid beta deposits and phospho\u2010tau neurofibrillary tangles, which drive inflammatory activation. RTP801, a stress\u2010responsive protein, has been implicated in mediating neuroinflammation. Its levels are increased in AD hippocampal samples, correlating with disease severity and cognitive decline.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Using astrocyte\u2010specific RTP801 silencing in the hippocampus of 5xFAD mice, we evaluated cognition, neuroinflammation, and hippocampal connectivity by magnetic resonance spectroscopy (MRS) and resting\u2010state functional connectivity analyses. Histological and biochemical analyses assessed microgliosis, astrogliosis, and inflammasome\u2010related protein levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Astrocytic RTP801 silencing in 5xFAD mice preserved spatial memory, maintained hippocampal \u03b3\u2010aminobutyric acid (GABA) levels, and preserved resting\u2010state brain networks. In addition, RTP801 silencing significantly reduced markers of microgliosis, astrogliosis, and inflammasome effectors.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Astrocytic RTP801 contributes to AD\u2010associated cognitive decline by disrupting GABAergic\u2010regulated connectivity and amplifying inflammatory responses. Targeting astrocytic RTP801 may therefore offer therapeutic potential to mitigate AD progression by preserving neural connectivity and reducing neuroinflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The 5xFAD mouse model of Alzheimer's disease presents higher levels of RTP801 in hippocampal astrocytes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Normalizing the levels of astrocytic RTP801 prevents cognitive decline and restores anxiety\u2010like behavior in the 5xFAD mouse model.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Knocking down astrocytic RTP801 preserves the resting\u2010state functional connectivity in the 5xFAD mouse model.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Astrocytic RTP801 mediates the loss of Parvalbumin+ interneurons, negatively affecting the levels of \u03b3\u2010aminobutyric acid (GABA) in the 5xFAD mouse model.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Astrocytic RTP801 contributes to astro\u2010 and microgliosis and inflammasome expression in the 5xFAD mouse model.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70051","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T02:10:22Z","timestamp":1746583822000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Astrocytes, via RTP801, contribute to cognitive decline by disrupting GABAergic\u2010regulated connectivity and driving neuroinflammation in an Alzheimer's disease mouse model"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5459-1065","authenticated-orcid":false,"given":"Almudena","family":"Chicote\u2010Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"Solana\u2010Balaguer","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pol","family":"Garcia\u2010Segura","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gen\u00eds","family":"Campoy\u2010Campos","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s P\u00e9rez","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"P\u00e9rez\u2010Navarro","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"},{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) Barcelona Catalonia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel J.","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"},{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) Barcelona Catalonia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Alberch","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"},{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) Barcelona Catalonia Spain"},{"name":"Faculty of Medicine and Health Science Production and Validation Center of Advanced Therapies (Creatio) University of Barcelona Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Giralt","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"},{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) Barcelona Catalonia Spain"},{"name":"Faculty of Medicine and Health Science Production and Validation Center of Advanced Therapies (Creatio) University of Barcelona Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Soria","sequence":"additional","affiliation":[{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) Barcelona Catalonia Spain"},{"name":"Brain Connectivity and Neuroimaging Lab Neuroscience Institute University of Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Bioingenier\u00eda, Biomateriales y Nanomedicina, C. de Melchor Fern\u00e1ndez Almagro, 3 Fuencarral\u2010El Pardo Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7185-436X","authenticated-orcid":false,"given":"Cristina","family":"Malagelada","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina Facultat de Medicina i Ci\u00e8ncies de la Salut Institut de Neuroci\u00e8ncies Universitat de Barcelona Barcelona Catalonia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae104"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)70016-5"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22930"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-25-08692.2003"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0616-08.2008"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30501-9"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00599-3"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22116068"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2023.07.009"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.7.2283-2293.2002"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1256804"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3928-08.2008"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3292-06.2006"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-02775-5"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom12010034"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2009.00688.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.06.073"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03899-y"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12887"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00557-1"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.116278"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2014.01.060"},{"key":"e_1_2_10_25_1","first-page":"2831","article-title":"Detection of neuritic plaques in Alzheimer's disease mouse model","author":"Ly PTT","year":"2011","journal-title":"J Vis Exp"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601417103"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp233"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2011.07.003"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/neuro.05.001.2008"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.07.024"},{"key":"e_1_2_10_31_1","article-title":"Resting state networks in the TGF344\u2010AD rat model of Alzheimer's disease are altered from early stages","volume":"10","author":"Tudela R","year":"2019","journal-title":"Front Aging Neurosci"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.22414"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2003.53"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2008.02.001"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08673"},{"key":"e_1_2_10_36_1","first-page":"2441","article-title":"Conditional BDNF delivery from astrocytes rescues memory deficits, spine density, and synaptic properties in the 5xFAD mouse model of Alzheimer disease","volume":"39","author":"De Pins B","year":"2019","journal-title":"J Neurosci"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2014.05.041"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10020305"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2013.02.071"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1162\/netn_a_00048"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.06.028"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44220-024-00259-5"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-143225"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2012-111889"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-010-0242-4"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00293459"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.47"}],"container-title":["Alzheimer's &amp; Dementia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.70051","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T20:57:50Z","timestamp":1759957070000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/alz.70051"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":46,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1002\/alz.70051"],"URL":"https:\/\/doi.org\/10.1002\/alz.70051","archive":["Portico"],"relation":{},"ISSN":["1552-5260","1552-5279"],"issn-type":[{"value":"1552-5260","type":"print"},{"value":"1552-5279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]},"assertion":[{"value":"2024-11-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70051"}}