Oxidative stress-mediated DHEA formation in Alzheimer's disease pathology.
An alternative pathway for dehydroepiandrosterone (DHEA) synthesis has been suggested by treating rat and human brain cells with ferrous sulfate and beta-amyloid (Abeta). 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 17alpha-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 FeSO(4) 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 FeSO(4) may serve as an indicator of AD pathology.
Brown
Rachel C
RC
The Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20007, USA.
Han
Zeqiu
Z
Cascio
Caterina
C
Papadopoulos
Vassilios
V
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000187:drug effects / Q000378:metabolism; D000704:Analysis of Variance; D015153:Blotting, Western; D003687:Dehydroepiandrosterone / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007501:Iron / Q000627:therapeutic use; D008297:Male; D016555:Matched-Pair Analysis; D018384:Oxidative Stress; D011282:Pregnenediones / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013440:Sulfides / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D011282:Pregnenediones; D012333:RNA, Messenger; D013440:Sulfides; C011342:pyrite; D003687:Dehydroepiandrosterone; D007501:Iron; D013254:Steroid 17-alpha-Hydroxylase