A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease

Anna E. Tschiffely, Rosemary A. Schuh, Katalin Prokai-Tatrai, Laszlo Prokai, Mary Ann Ottinger

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)39-44
Number of pages6
JournalHormones and Behavior
Volume83
DOIs
StatePublished - 1 Jul 2016

Fingerprint

Prodrugs
Transgenic Mice
Estradiol
Alzheimer Disease
Brain
Hormones
Amyloid beta-Protein Precursor
Ovariectomy
Amyloid
Estrogens
Therapeutics
Pathology
Weights and Measures
Peptides
Proteins

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Brain-selective prodrug
  • Estradiol
  • Radial arm water maze
  • Transgenic mice

Cite this

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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 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.",
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A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease. / Tschiffely, Anna E.; Schuh, Rosemary A.; Prokai-Tatrai, Katalin; Prokai, Laszlo; Ottinger, Mary Ann.

In: Hormones and Behavior, Vol. 83, 01.07.2016, p. 39-44.

Research output: Contribution to journalArticleResearchpeer-review

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

PY - 2016/7/1

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KW - Amyloid-β

KW - Brain-selective prodrug

KW - Estradiol

KW - Radial arm water maze

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SN - 0018-506X

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