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Yet, the therapeutic options for addressing the disease pathogenesis are limited. Here, we report an approach by targeting brain nucleoside homeostasis and energy metabolism to alleviate AD\u2010associated cognitive deficits. A compound, J4, was designed to modulate nucleoside homeostasis by interacting with the equilibrative nucleoside transporter\u20101 (ENT1). The effects of J4 on brain nucleoside homeostasis and energy metabolism were examined in mice. Two AD animal models, THY\u2010Tau22 and APP\/PS1 mice, were used to evaluate the translational potential of J4 for the treatment of AD. Cognitive function and functional ability were assessed using the Morris water maze, Y\u2010maze, and nesting behavior tests. The pharmacodynamic marker was explored, and the pharmacokinetic and safety properties of J4 were evaluated. As a result, being administered after disease onset, oral J4 administration rescued memory and cognitive dysfunction in both tau and amyloid AD mouse models. Metabolomic analysis showed that J4 increased brain nucleoside levels and facilitated brain primary metabolism, including glucose metabolism and the pentose phosphate pathway. The [<jats:sup>18<\/jats:sup>F]\u2010fluorodeoxyglucose positron emission tomography (FDG\u2010PET) imaging further demonstrated that glucose metabolism can be used as a pharmacodynamic biomarker for the target engagement of J4 on ENT1. The nonclinical studies also demonstrated the ideal pharmacokinetic and safety profiles of J4, supporting that targeting nucleoside homeostasis can improve brain energy metabolism and is a promising approach for AD treatment.<\/jats:p>","DOI":"10.1002\/prp2.70176","type":"journal-article","created":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T04:10:12Z","timestamp":1759637412000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Preclinical Evaluation of a Novel Molecule Targeting Nucleoside Homeostasis to Restore Energy Metabolism and Cognitive Function in Alzheimer's Disease"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3165-120X","authenticated-orcid":false,"given":"Kuo\u2010Chen","family":"Wu","sequence":"first","affiliation":[{"name":"School of Pharmacy, College of Medicine National Taiwan University  Taipei Taiwan"},{"name":"Biomedical Translation Research Center Academia Sinica  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien\u2010Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Biomedical Translation Research Center Academia Sinica  Taipei Taiwan"},{"name":"Institute of Biomedical Sciences Academia Sinica  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanh","family":"Tran","sequence":"additional","affiliation":[{"name":"Taiwan International Graduate Program (TIGP\u2010CBMB) Academia Sinica  Taipei Taiwan"},{"name":"Institute of Biochemical Sciences National Taiwan University  Taipei Taiwan"},{"name":"Research Center for Applied Sciences Academia Sinica  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung\u2010Hsing","family":"Lin","sequence":"additional","affiliation":[{"name":"Biomedical Translation Research Center Academia Sinica  Taipei Taiwan"},{"name":"Research Center for Applied Sciences Academia Sinica  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin\u2010Hsien","family":"Yeh","sequence":"additional","affiliation":[{"name":"School of Medicine National Defense Medical Center  Taipei Taiwan"},{"name":"Brain Research Center National Yang Ming Chaio Tung University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin\u2010Jui","family":"Ho","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijuang","family":"Chern","sequence":"additional","affiliation":[{"name":"Biomedical Translation Research Center Academia Sinica  Taipei Taiwan"},{"name":"Institute of Biomedical Sciences Academia Sinica  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Jung","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12385"},{"issue":"5","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1001\/jama.2022.24490","article-title":"Lecanemab Gains FDA Approval for Early Alzheimer Disease","volume":"329","author":"Larkin H. 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