Oxidative stress-mediated DHEA formation in Alzheimer’s disease pathology

Abstract 

An alternative pathway for dehydroepiandrosterone (DHEA) synthesis has been suggested by treating rat and human brain cells with ferrous sulfate and β-amyloid (Aβ). To determine if this pathway exists in human brain, levels of DHEA in hippocampus, hypothalamus and frontal cortex from Alzheimer’s disease (AD) patients and age-matched controls were measured. DHEA is significantly higher in AD brain than control, and was highest in AD hippocampi. Cytochrome P450 17α-hydroxylase, responsible for peripheral DHEA synthesis, is not present in hippocampus. DHEA levels in AD cerebrospinal fluid (CSF) were significantly higher than age-matched controls. AD serum DHEA levels are lower than CSF, and not significantly different from controls. Treatment of control hippocampus, hypothalamus and serum with FeSO₄ increases DHEA, suggesting that levels of precursor are higher in control that in AD brain. This suggests that (i) an alternative precursor is present in control brain, (ii) AD brain DHEA is formed by oxidative stress metabolism of precursor, and (iii) CSF DHEA levels and serum DHEA formation in response to FeSO₄ may serve as an indicator of AD pathology.

Abbreviations:  DHEA, 3β-hydroxy-5-androsten-17-one or dehydroepiandrosterone, P450c17, cytochrome P450 17α-hydroxylase, Aβ, β-amyloid peptide, AD, Alzheimer’s disease, FeSO₄, ferrous sulfate, ROS, reactive oxygen species, CSF, cerebrospinal fluid

Keywords:  DHEA, Oxidative stress, Cytochrome P450c17, Alzheimer’s disease, β-Amyloid