ABSTRACT

Among neurosteroids, DHEA is produced in the brain by a non-enzymatic mechanism involving Fe⁺⁺, free radicals and other unknown partners. This process is significantly aggravated by the β-amyloid protein. In human brain neurons, DHEA is a substrate for a sulphotransferase that produces DHEA-sulphate, and for cytochrome P4507B1 that produces major and minor quantities of 7α-hydroxy-DHEA and  7β-hydroxy-DHEA. Neuroprotective potencies have been found for these DHEA metabolites. Measurement of DHEA-sulphate, DHEA, 7α-hydroxy-DHEA and 7β-hydroxy-DHEA levels in the cerebrospinal fluid from patients with Alzheimer’s disease (AD), and comparison with levels from control subjects showed that DHEA levels were increased in AD with no increase in DHEA metabolites. These results indicate that lesser amounts of neuroprotective 7-hydroxylated and sulphated DHEA metabolites are available in AD brain and that the keys to their production are the brain cytochrome P4507B1 and the brain sulphotransferase. In AD brain, these enzymes may either be present at lower levels or be transformed through natural polymorphism into less efficient enzymes.