Dose-dependent and sequence-sensitive effects of amyloid-β 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 mu M 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 [H-3]progesterone but increased [H-3]estradiol production from the precursor [H-3]pregnenolone. Non-toxic A beta(25-35) doses reduced [H-3]progesterone formation but had no effect on [H-3]estradiol biosynthesis. At 12 mu M, both A beta(1-42) and A beta(25-35) inhibited [H-3]progesterone formation but only A beta(1-42) reduced [H-3]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. (C) 2008 Elsevier Ltd. All rights reserved.