Effect of estradiol on neuronal Swedish-mutated beta-amyloid precursor protein metabolism: reversal by astrocytic cells.
Alzheimer's disease is the most frequent neurodegenerative disorder in the aged population and is characterized by the deposition of the 40/42-residue amyloid beta protein (Abeta), a proteolytic fragment of the beta-amyloid precursor protein (APP). Recently, it has been shown that physiological doses of estradiol reduce the generation of endogenous Abeta in primary cortical neurons. Here we investigate the influence of estrogen in amyloidogenesis and sAPPalpha secretion in the CNS. By means of primary cortical neurons overexpressing humanized APP(695) bearing the Swedish mutation (hAPP(695sw)), we analyzed APP maturation in the absence or in the presence of estrogen. We show that estrogen at a 2 microM concentration increases the release of the neuroprotective sAPPalpha fragment but does not reduce the release of Abeta in primary neurons overexpressing the Swedish-mutated form of APP. Furthermore, neurons cocultured with astrocytic cells or grown with astrocytes conditioned media do not exhibit the estrogen-induced increase in sAPPalpha secretion. Altogether, our data indicate that astrocytes interfere with estrogen in the regulation of sAPPalpha secretion, probably via secreted factor(s).
Vincent
B
B
Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA. vincentb@ipmc.cnrs.fr
Smith
J D
JD
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism* / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism / Q000502:physiology*; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011233:Precipitin Tests
D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D004958:Estradiol