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Ovariectomy and 17β-Estradiol Replacement Do Not Alter β-Amyloid Levels in Sheep Brain

School of Psychiatry and Clinical Neurosciences (A.M.B., G.V., R.N.M.), The University of Western Australia, and Sir James McCusker Alzheimer’s Disease Research Unit (A.M.B., G.V., R.N.M.), School of Psychiatry and Clinical Neurosciences and University of Western Australia, Hollywood Private Hospital, Nedlands 6009, Australia; Centre of Excellence in Alzheimer’s Disease Research and Care (A.M.B., G.V., R.N.M.), Edith Cowan University, Joondalup 6027, Australia; and School of Veterinary and Biomedical Sciences (M.C.), Murdoch University, Perth, Western Australia 6105, Australia

Address all correspondence and requests for reprints to: Professor Ralph N. Martins, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, 100 Joondalup Drive, Joondalup, Western Australia 6027, Australia. E-mail: r.martins{at}ecu.edu.au.

The benefits of estrogen replacement as a preventative treatment for Alzheimer’s disease (AD) are subject to debate. Because the effects of estrogen depletion and replacement on accumulation of the neurotoxic β-amyloid (Aβ) peptide in transgenic animal models of AD have been variable, we examined Aβ levels and oxidative stress in a nontransgenic animal model. Sheep have traditionally been used as a model for human reproduction; however because they share 100% sequence homology with the human form of Aβ, they may also have potential as a nontransgenic model for Aβ biology. The effect of ovariectomy and estrogen replacement administered for 6 months via slow-release implant was examined in the brain of 4.5-yr-old sheep. Aβ levels were measured by ELISA, and protein levels of the amyloid precursor protein (APP), APP C-terminal fragments (C100), and presenilin-1 were examined semiquantitatively by Western blot as markers of APP processing. Markers of oxidative stress were examined semiquantitatively by Western blot [4-hydroxy-2(E)-nonenal] and oxyblot (protein carbonyls). We found no effects of estrogen depletion and supplementation in terms of AD-related biochemical markers, including Aβ levels, APP processing, and oxidative stress levels. Evidence of a trend toward increased P450 side-chain cleavage enzyme levels in the hippocampus of ovariectomized and estrogen supplemented sheep suggests that neurosteroidogenesis may compensate for gonadal estrogen depletion; however, these findings cannot explain the lack of effect of estrogen supplementation on APP processing. It is possible that supraphysiological doses of estrogen are necessary to yield antiamyloidogenic and antioxidative benefits in ovariectomized sheep.