Dose-dependent and sequence-sensitive effects of amyloid-beta peptide on neurosteroidogenesis in human neuroblastoma...

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.