Dose-dependent and sequence-sensitive effects of amyloid-beta peptide on neurosteroidogenesis in human neuroblastoma cells.
Interactions between neurosteroidogenesis and proteins involved in age-related diseases are unknown. High concentrations of amyloid-beta (A beta) peptides induce plaques in Alzheimer's disease but several studies demonstrated that physiological or non-toxic doses are neuroprotective. We compared the effects of non-toxic and toxic concentrations of A beta 1-42 and A beta 25-35 on neurosteroidogenesis in human neuroblastoma SH-SY5Y cells. Viability assays revealed that nanomolar doses of A beta are devoid of cytotoxicity while 12 microM induced cell death. Pulse-chase, high-performance liquid chromatography and flow-scintillation analyses showed that non-toxic A beta 1-42 concentrations, acting selectively, decreased [3H]progesterone but increased [3H]estradiol production from the precursor [3H]pregnenolone. Non-toxic A beta 25-35 doses reduced [3H]progesterone formation but had no effect on [3H]estradiol biosynthesis. At 12 microM, both A beta 1-42 and A beta 25-35 inhibited [3H]progesterone formation but only A beta 1-42 reduced [3H]estradiol production. The results demonstrate a selective and amino-acid sequence-dependent action of A beta on neurosteroidogenesis. The fact that non-toxic A beta 1-42 doses stimulated neuroprotective-neurosteroid estradiol synthesis, which is inhibited by high A beta 1-42 doses, may explain A beta 1-42 ability to exert either protective or deleterious effects on nerve cells.
Schaeffer
Véronique
V
Equipe Stéroïdes et Système Nociceptif, Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique/Université Louis Pasteur, 21 rue René Descartes, 67084 Strasbourg Cedex, France.
Meyer
Laurence
L
Patte-Mensah
Christine
C
Eckert
Anne
A
Mensah-Nyagan
Ayikoe G
AG
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000096:biosynthesis; D006801:Humans; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000096:biosynthesis; D013256:Steroids / Q000096:biosynthesis*
D016229:Amyloid beta-Peptides; D004967:Estrogens; D010446:Peptide Fragments; D013256:Steroids; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D011374:Progesterone; D011284:Pregnenolone