Characterization of alpha1-antitrypsin as a heme oxygenase-1 suppressor in Alzheimer plasma.
Heme oxygenase-1 (HO-1) mRNA and protein levels are diminished in Alzheimer disease (AD) blood, cerebrospinal fluid (CSF) and choroid plexus. Herein, the presence of a heme oxygenase-1 suppressor (HOS) factor was ascertained by astroglial bioassay, biochemical techniques and immunofluorescence confocal microscopy. We report significantly augmented plasma HOS activity in AD patients relative to healthy elderly and neurological controls. The HOS factor was determined to be a 50-100 kDa heat-labile, heparin-binding glycoprotein that is unrelated to antioxidant ingestion, plasma total antioxidant capacity, circulating cortisol levels or apolipoprotein E epsilon4 carrier status. HOS bioactivity was recapitulated by exogenous alpha(1)-antitrypsin. alpha(1)-antitrypsin levels were significantly increased in AD plasma and correlated with HOS activity and MMSE scores. alpha(1)-antitrypsin immunodepletion attenuated HOS activity of AD plasma. In AD brain, alpha(1)-antitrypsin immunoreactivity was augmented and co-distributed with HO-1. HOS activity of alpha(1)-antitrypsin may curtail HO-1-dependent derangement of cerebral iron homeostasis and account for diminished HO-1 expression in AD peripheral tissues.
Maes
Olivier C
OC
Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Chemin Cote Ste-Catherine Montreal, Canada H3T1E2.
Kravitz
Steven
S
Mawal
Yogesh
Y
Su
Haixiang
H
Liberman
Adrienne
A
Mehindate
Khalil
K
Berlin
Dan
D
Sahlas
Demetrios J
DJ
Chertkow
Howard M
HM
Bergman
Howard
H
Melmed
Calvin
C
Schipper
Hyman M
HM
D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015152:Blotting, Northern; D001921:Brain / Q000473:pathology; D002831:Choroid Plexus / Q000378:metabolism; D002846:Chromatography, Affinity; D003072:Cognition Disorders / Q000097:blood / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005455:Fluorescent Antibody Technique; D016153:Genes, Suppressor; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D018613:Microscopy, Confocal; D008875:Middle Aged; D009483:Neuropsychological Tests; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000502:physiology*
D000975:Antioxidants; D018076:DNA, Complementary; D012333:RNA, Messenger; D000515:alpha 1-Antitrypsin; D051547:Heme Oxygenase-1; D006854:Hydrocortisone