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Nrf2 is a master controller of homeostatic functions whose activity is compromised in AD. Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify cysteine residues in the thiol\u2010rich Keap1, and many are Michael acceptors, such as low\u2010molecular\u2010weight (LMW) skin allergens. However, LMW allergens\u2010induced Nrf2 activation in a pharmacological setting has only recently attracted attention, exemplified by the clinical success of Dimethyl Fumarate. Hence, we investigated, for the first time, the potential of the skin allergen Isoeugenol to activate Nrf2 and reverse selected AD hallmarks, both in\u00a0vitro and in\u00a0vivo, in AD\u2010specific models. In\u00a0vitro studies were performed using microglia cells exposed to LPS and neuronal cells overexpressing human APP with Swedish mutation, to evaluate Isoeugenol's potential in decreasing neuroinflammation and activating the Nrf2 pathway, respectively. In\u00a0vivo studies were conducted in 10\u2010month\u2010old AD double\u2010transgenic mice (APP\/PS1), which were intranasally administered Isougenol. Isoeugenol's pharmacokinetic and pharmacodynamic profile, and its effect on mice cognition were evaluated. The results showed that Isoeugenol (1) activated Nrf2 in AD neuronal cells (likely involving AKT signaling); (2) exhibited antioxidant and Nrf2\u2010dependent anti\u2010inflammatory activity, which was abolished after Nrf2 silencing; (3) exhibited good pharmacokinetic and pharmacodynamic profiles; (4) reduced the levels of A\u03b2 peptides in\u00a0vitro and in\u00a0vivo; (5) reduced triglyceride and LDL cholesterol levels in treated mice; and (6) improved the memory deficits in old mice. This is the first study reporting Isoeugenol's intranasal administration, and on specific AD mice models. Overall, the results reinforce Isoeugenol as a pleiotropic molecule, with great potential for AD treatment.<\/jats:p>","DOI":"10.1096\/fj.202601575r","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:59:01Z","timestamp":1785833941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intranasal Administration of Isoeugenol Improves Memory Deficits in\n                    <scp>APP<\/scp>\n                    \/\n                    <scp>PS1<\/scp>\n                    Old Mice\u2014A Role Beyond Nrf2 Activation?"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-0376","authenticated-orcid":false,"given":"Ana","family":"Silva","sequence":"first","affiliation":[{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB) University of Coimbra  Coimbra Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC\u2010UC) University 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