| Neurosteroids in rodents can originate from peripheral tissues or be locally synthesized in specific brain areas. There is no information about synthesis and regulation of neurosteroids in human brain. We examined the ability of human brain to synthesize steroids from a radiolabeled precursor, and mRNA and protein expression of key components of steroidogenic machinery. Oligodendrocytes are the source of pregnenolone in human brain; their steroidogenic ability is regulated by the subcellular localization of the peripheral-type benzodiazepine receptor. Human astrocytes do not synthesize radiolabeled pregnenolone, nor do human neurons. All three cell types may metabolize pregnenolone to other neurosteroids, including dehydroepiandrosterone (D). mRNA and protein for cytochrome P450 17alpha-hydroxylase was found in all cell types although no activity could be demonstrated. We examined the ability of the cells to make D via an alternative pathway induced by treatment with Fe++. Oligodendrocytes and astrocytes make D via this pathway, but neurons do not. In searching for a natural regulator of D formation, we observed that treating oligodendrocytes with beta-amyloid, which increases reactive oxygen species, also increased D formation. These effects were blocked by Vitamin E. This indicates that human brain makes steroids in a cell-specific manner, and suggests that D synthesis is regulated by intracellular free radicals.;Alzheimer's disease (AD) involves oxidative stress. We measured levels of D in hypothalamus, hippocampus and frontal cortex from patients with AD and controls. Levels of D are significantly higher in all regions of AD brain compared to control. However, P450 17alpha-hydroxylase is absent from the hippocampus. It seems likely that D in this area is produced entirely by the activity of the oxidative stress-mediated alternative pathway acting on an as yet unidentified precursor. Treatment of AD brain with Fe++ has no effect on D levels, while control brain treated with Fe++ has higher levels of D, indicating that in AD brain, there is no available pool of alternative precursor. Finally, levels of D in the cerebrospinal fluid of AD patients are significantly higher then controls. This indicates that D is formed in the AD brain by oxidative stress-mediated metabolism of the unknown steroid precursor. |
