In vitro metabolism of dehydroepiandrosterone (DHEA) to 7alpha-hydroxy-DHEA and Delta5-androstene-3beta,17beta-diol in specific regions of the aging brain from Alzheimer's and non-demented patients.
The description of dehydroepiandrosterone (DHEA) as a neuroactive neurosteroid has raised the important question of whether the steroid itself and/or its metabolite(s) are active in the brain. Classical transformations of DHEA in brain and peripheral tissues include its conversion to testosterone and estradiol. In the human brain, the metabolism of DHEA to other metabolites is still poorly understood, particularly in aging people and Alzheimer's patients. The present study describes the in vitro transformation of DHEA into 7alpha-hydroxy-DHEA and Delta5-androstene-3beta,17beta-diol, for the first time in the aging brain of patients with Alzheimer's disease in comparison with non-demented controls. Formal identification of DHEA metabolites is provided by gas chromatography-mass spectrometry, thus indicating the presence of NADPH-dependent 7alpha-hydroxylase and 17beta-hydroxysteroid oxidoreductase activities. Under our experimental conditions, the synthesis of 7alpha-hydroxy-DHEA and Delta5-androstene-3beta,17beta-diol occurs in the frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and non-demented controls. In both groups of patients, the pattern of DHEA metabolism is similar, but significant higher synthesis of 7alpha-hydroxy-DHEA in the frontal cortex and Delta5-androstene-3beta,17beta-diol in the cerebellum and striatum were observed compared with those in other brain regions. In addition, a trend toward a significant negative correlation is found between the density of cortical amyloid deposits and the amount of 7alpha-hydroxy-DHEA formed in the frontal cortex and that of Delta5-androstene-3beta,17beta-diol in the hippocampus. Therefore, the biosynthesis of 7alpha-hydroxy-DHEA and/or Delta5-androstene-3beta,17beta-diol is likely to regulate DHEA cerebral concentrations and may contribute to the control of DHEA activity in the aging brain including in Alzheimer's disease.
Weill-Engerer
Sébastien
S
INSERM U488, Stéroides et Système Nerveux, 80 Rue du Général Leclerc, 94276, Le Kremlin-Bicêtre, France.
David
Jean Philippe
JP
Sazdovitch
Véronique
V
Liere
Philippe
P
Schumacher
Michael
M
Delacourte
André
A
Baulieu
Etienne Emile
EE
Akwa
Yvette
Y
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism; D015114:Androstenediol / Q000032:analysis; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D065637:Cytochrome P-450 CYP2A6; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology
D003687:Dehydroepiandrosterone; C003587:7-hydroxydehydroepiandrosterone; D015114:Androstenediol; D006899:Mixed Function Oxygenases; D015067:17-Hydroxysteroid Dehydrogenases; C045839:androstenedione 17-alpha-oxidoreductase; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6