Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of aggregated forms of the 40- and 42-amino acid Abeta peptides (Abeta40 and Abeta42). Estrogen replacement therapy (ERT) in postmenopausal women is associated with decreased risk for AD and/or delay in disease onset. The mechanism by which estrogen exerts this neuroprotective effect is elusive. 17beta-estradiol (E2) was shown to reduce the release of Abeta peptides by primary neuronal cultures of murine and human origin. To test whether estrogen can modulate the metabolism of Abeta peptides in vivo, four experimental sets of guinea pigs were used: intact animals, ovariectomized animals, and ovariectomized animals that received E2 at two different doses. Ovariectomy was associated with a 1.5-fold average increase in total brain Abeta levels as compared to intact controls. E2 treatment significantly reversed the ovariectomy-induced increase in brain Abeta levels. The high-dose E2 treatment did not lead to further decrease in brain Abeta beyond the one observed with the low-dose E2 treatment. Our results infer that cessation of ovarian estrogen production in postmenopausal women might facilitate Abeta deposition by increasing the local concentrations of Abeta40 and Abeta42 peptides in brain and suggest that modulation of Abeta metabolism may be one of the ways by which ERT prevents and/or delays the onset of AD in postmenopausal women.
Petanceska
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Nathan Kline Institute, 140 Old Orangeburg Road, 10962, Orangeburg, NY 10962, USA.
Nagy
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Frail
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Gandy
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D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D010052:Ovariectomy; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D004958:Estradiol