title: A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease.
abstract: Estrogens are neuroprotective and, thus, potentially useful for the therapy of Alzheimer's disease; however, clinical use of hormone therapy remains controversial due to adverse peripheral effects. The goal of this study was to investigate the benefits of treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, in comparison with the parent hormone using APPswe/PS1dE9 double transgenic mice to model the pathology of the disease. Ovariectomized and intact females were continuously treated with vehicle, 17β-estradiol, or DHED via subcutaneous osmotic pumps from 6 to 8months of age. We confirmed that this prolonged treatment with DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment increased uterine weight. Amyloid precursor protein decreased in both treatment groups of intact, but not in ovariectomized double transgenic females in which ovariectomy already decreased the expression of this protein significantly. However, reduced brain amyloid-β peptide levels could be observed for both treatments. Consequently, double-transgenic ovariectomized and intact mice had higher cognitive performance compared to untreated control animals in response to both estradiol and DHED administrations. Overall, the tested brain-selective 17β-estradiol prodrug proved to be an effective early-stage intervention in an Alzheimer's disease-relevant mouse model without showing systemic impact and, thus, warrants further evaluation as a potential therapeutic candidate.
authors.affiliation: Neuroscience and Cognitive Science Graduate Program, University of Maryland College Park, MD 20742, USA; Department of Animal and Avian Sciences, University of Maryland College Park, MD 20742, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Tschiffely
authors.affiliation: Research Service, VAMHCS, Baltimore, MD 21201, USA; Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Schuh
authors.affiliation: Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; AgyPharma LLC, Mansfield, TX 76063, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Prokai-Tatrai
authors.affiliation: Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; AgyPharma LLC, Mansfield, TX 76063, USA. Electronic address: Laszlo.Prokai@unthsc.edu.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Prokai
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland College Park, MD 20742, USA. Electronic address: maotting@central.uh.edu.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Ottinger
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D009928:Organ Specificity; D010052:Ovariectomy; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D011355:Prodrugs; D004958:Estradiol
keywords: Alzheimer's disease; Amyloid-β; Brain-selective prodrug; Estradiol; Radial arm water maze; Transgenic mice