TY - JOUR
T1 - A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease
AU - Tschiffely, Anna E.
AU - Schuh, Rosemary A.
AU - Prokai-Tatrai, Katalin
AU - Prokai, Laszlo
AU - Ottinger, Mary Ann
N1 - Funding Information:
This research funded by the National Institutes of Health grants AG031387 (MAO) and AG031535 (LP), the Robert A. Welch Foundation (endowment BK-0031 , LP), the VA Research Service Rehabilitation R&D REAP (RAS), and the Biomedical R&D CDA02 (RAS), and was conducted in partial fulfillment of the Ph.D. requirements for the University of Maryland (AET). L.P. and K.P.-T. have equity interests in AgyPharma LLC and are co-inventors of US Patents 7,026,306 and 7,300,926 on the use of DHED. All other authors disclose no financial interest or potential conflicts of interest.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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 8 months 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.
AB - 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 8 months 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.
KW - Alzheimer's disease
KW - Amyloid-β
KW - Brain-selective prodrug
KW - Estradiol
KW - Radial arm water maze
KW - Transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=84975089427&partnerID=8YFLogxK
U2 - 10.1016/j.yhbeh.2016.05.009
DO - 10.1016/j.yhbeh.2016.05.009
M3 - Article
C2 - 27210479
AN - SCOPUS:84975089427
SN - 0018-506X
VL - 83
SP - 39
EP - 44
JO - Hormones and Behavior
JF - Hormones and Behavior
ER -