{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:26:40Z","timestamp":1788269200912,"version":"build-2803163510"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T00:00:00Z","timestamp":1594252800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81773717"],"award-info":[{"award-number":["81773717"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["8144111"],"award-info":[{"award-number":["8144111"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81601229"],"award-info":[{"award-number":["81601229"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key R & D Plan of Shandong Province","award":["2019GSF108037"],"award-info":[{"award-number":["2019GSF108037"]}]},{"name":"Academic Promotion Programme of Shandong First Medical University","award":["2019LJ003"],"award-info":[{"award-number":["2019LJ003"]}]},{"name":"Academic Promotion Programme of Shandong First Medical University","award":["2019QL011"],"award-info":[{"award-number":["2019QL011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Depression is highly related to Alzheimer\u2019s disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe\/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In the novel object recognition and Morris water-maze, APPswe\/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg\/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin\u2013eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2\/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B\/PDE4D-mediated cAMP\/cAMP response element-binding protein\/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ijnp\/pyaa048","type":"journal-article","created":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T11:10:58Z","timestamp":1594206658000},"page":"700-711","source":"Crossref","is-referenced-by-count":83,"title":["The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer\u2019s Disease: A Preclinical Study in APP\/PS1 Transgenic Mice"],"prefix":"10.1093","volume":"23","author":[{"given":"Hao","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-rong","family":"Fu","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-dan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-yan","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-feng","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-guo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Ting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Behavioral Medicine & Psychiatry, the Rockefeller Neuroscience Institute, West Virginia University Health Sciences Center, Morgantown, West Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,9]]},"reference":[{"key":"2020121009533731800_CIT0001","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s10339-011-0430-z","article-title":"The novel object recognition memory: neurobiology, test procedure, and its 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