{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T08:06:57Z","timestamp":1789546017762,"version":"build-2803163510"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) imposes a significant global healthcare burden, and current available pharmacotherapies provide limited therapeutic benefits. Disrupted phosphodiesterase 5 (PDE5) signaling has been implicated in the pathogenesis of AD and other neurodegenerative disorders, positioning PDE5 inhibitors (PDE5Is) as a promising therapeutic strategy for AD treatment. This study evaluated the preclinical therapeutic potential of aildenafil citrate (AC), a selective PDE5I approved in China for the treatment of erectile dysfunction (ED), in AD treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were integrated to explore the molecular mechanisms of aildenafil. The APP\/PS1 transgenic mouse model of AD was employed to assess the in vivo efficacy of AC through behavioral, pathological, and oxidative assessments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In silico analyses indicated that aildenafil exhibited a higher predicted affinity through a strengthened electrostatic network anchored by key bidentate hydrogen bonds with Gln817 and enhanced \u03c0\u2010\u03c0 stacking interactions with Phe820. Behavioral assessments, including the Barnes maze and Open field tests, demonstrated that AC significantly ameliorates cognitive dysfunction and anxiety-like impairments. Pathological examinations revealed improved hippocampal morphology, upregulated neprilysin (NEP) expression, and reduced A\u03b2 accumulation. The decreased malondialdehyde (MDA) levels further suggested a potential attenuation of systemic oxidative stress and provided preliminary support for further investigation into its effects on central redox status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings offer an initial phenotypic characterization of AC in an AD mouse model, underscoring the need for comprehensive mechanistic studies to fully evaluate its potential as a repurposed AD therapeutic candidate.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1933588","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:43:42Z","timestamp":1789544622000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Aildenafil citrate with superior PDE5 selectivity ameliorates cognitive and behavioral impairments in APP\/PS1 Alzheimer\u2019s disease mice: a preclinical phenotypic study"],"prefix":"10.3389","volume":"17","author":[{"given":"Shaowei","family":"Han","sequence":"first","affiliation":[{"name":"Beijing Youcare Kechuang Pharmaceutical Technology Co., Ltd.","place":["Beijing, China"]},{"name":"Youcare Pharmaceutical Group Hangzhou Tianlong Pharmaceutical Co.,Ltd., Hangzhou","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Youcare Kechuang Pharmaceutical Technology Co., Ltd.","place":["Beijing, China"]},{"name":"Youcare Pharmaceutical Group Hangzhou Tianlong Pharmaceutical Co.,Ltd., Hangzhou","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawei","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Youcare Kechuang Pharmaceutical Technology Co., Ltd.","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengshen","family":"Song","sequence":"additional","affiliation":[{"name":"Beijing Youcare Kechuang Pharmaceutical Technology Co., Ltd.","place":["Beijing, China"]},{"name":"Youcare Pharmaceutical Group Hangzhou Tianlong Pharmaceutical Co.,Ltd., Hangzhou","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"111128","DOI":"10.1016\/j.biopha.2020.111128","article-title":"Phosphodiesterase 5 (PDE5): structure-function regulation and therapeutic applications of inhibitors","volume":"134","author":"Ahmed","year":"2021","journal-title":"Biomed. 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