{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:24:34Z","timestamp":1787498674449,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Estetra SRL"},{"name":"Gedeon Richter, the Freiwillige Akademische Gesellschaft (FAG) Basel"},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2025\/13590-8"],"award-info":[{"award-number":["2025\/13590-8"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mitochondrial dysfunction is an early driver of Alzheimer\u2019s disease (AD), and the decline in sex hormones, including 17\u03b2-estradiol (E2), at menopause has been linked to AD risk in women. While E2 exerts potent neuroprotective and mitochondrial-regulatory effects, its clinical utility in estrogen replacement therapy (ERT) may be limited by thrombotic and oncologic risks. Estetrol (E4), a fetal estrogen with a selective safety profile, may represent a promising alternative. This study evaluated the impact of E4 on mitochondrial bioenergetics and neuronal morphology in human SH-SY5Y neuroblastoma cells, including models of AD-related amyloidopathy (amyloid precursor protein overexpression) and tauopathy (P301Ltau mutation overexpression). E4 significantly enhanced ATP levels, mitochondrial membrane potential, and oxidative respiration in all cell models, notably outperforming E2 in P301L cells. E4 also promoted significant neurite outgrowth, alleviating deficits observed in AD models. In addition, we demonstrated that the bioenergetic effects of E4 were mediated by the estrogen receptors ER\u03b1, ER\u03b2, and GPER1. Furthermore, E4 modulated the expression of key mitochondrial genes, specifically upregulating the phosphate carrier SLC25A23 while downregulating the complex I subunit NDUFA1. In conclusion, E4 improves mitochondrial health and supports neuronal integrity via a multi-receptor mechanism, highlighting its potential as a safe neuroprotective therapy for AD.<\/jats:p>","DOI":"10.3390\/cells15050452","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T14:42:47Z","timestamp":1772548967000},"page":"452","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Estetrol Enhances Mitochondrial Bioenergetics and Neurite Outgrowth in Cellular Models of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3323-1756","authenticated-orcid":false,"given":"Amandine","family":"Grimm","sequence":"first","affiliation":[{"name":"Research Cluster Molecular & Cognitive Neuroscience, Department of Biomedicine, University of Basel, 4002 Basel, Switzerland"},{"name":"Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics Basel (UPK), 4002 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1056-1178","authenticated-orcid":false,"given":"Aur\u00e9lien","family":"Riou","sequence":"additional","affiliation":[{"name":"Research Cluster Molecular & Cognitive Neuroscience, Department of Biomedicine, University of Basel, 4002 Basel, Switzerland"},{"name":"Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics Basel (UPK), 4002 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Gaillard","sequence":"additional","affiliation":[{"name":"Research Cluster Molecular & Cognitive Neuroscience, Department of Biomedicine, University of Basel, 4002 Basel, Switzerland"},{"name":"Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics Basel (UPK), 4002 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Broeglin","sequence":"additional","affiliation":[{"name":"Research Cluster Molecular & Cognitive Neuroscience, Department of Biomedicine, University of Basel, 4002 Basel, Switzerland"},{"name":"Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics Basel (UPK), 4002 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3371-3376","authenticated-orcid":false,"given":"Rodrigo Portes","family":"Ureshino","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Federal University of Sao Paulo, Diadema 09972-270, SP, Brazil"},{"name":"Laboratory of Molecular and Translational Endocrinology, Escola Paulista de Medicina, Federal University of Sao Paulo, Sao Paulo 04039-22, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Dion","sequence":"additional","affiliation":[{"name":"Estetra SRL, a Wholly Owned Subsidiary of Gedeon Richter Plc., 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"G\u00e9rard","sequence":"additional","affiliation":[{"name":"Estetra SRL, a Wholly Owned Subsidiary of Gedeon Richter Plc., 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9341-3669","authenticated-orcid":false,"given":"Anne","family":"Eckert","sequence":"additional","affiliation":[{"name":"Research Cluster Molecular & Cognitive Neuroscience, Department of Biomedicine, University of Basel, 4002 Basel, Switzerland"},{"name":"Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics Basel (UPK), 4002 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.molmed.2012.12.007","article-title":"Estrogen synthesis and signaling pathways during aging: From periphery to brain","volume":"19","author":"Cui","year":"2013","journal-title":"Trends Mol. 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