Astroglial heme oxygenase-1 and the origin of corpora amylacea in aging and degenerating neural tissues.
BACKGROUND
Corpora amylacea (CA) are glycoproteinaceous (predominantly glial and extracellular) inclusions that accumulate in normal aging brain and, to a greater extent, in Alzheimer disease (AD). Previous pharmacological evidence suggested that up-regulation of endogenous heme oxygenase-1 (HO-1) in astrocytes promotes transformation of normal mitochondria to CA-like inclusions. Here, we determined whether 1) HMOX1 transfection fosters the accumulation of CA-like inclusions in cultured rat astroglia; 2) the HMOX1 transgene promotes CA formation in the brains of aging GFAP.HMOX1 mice; and 3) brain mitochondrial damage and CA biogenesis are augmented in persons with mild cognitive impairment (MCI), a harbinger of AD.


METHODS
CA were ascertained in (i) neonatal rat astroglia transfected with flag-tagged human HO-1 cDNA, (ii) brain sections derived from 19month-old GFAP.HMOX1 and wild-type (WT) mice, and (iii) post-mortem hippocampal sections from individuals with mild (MCI) and no cognitive impairment (NCI) after staining with PAS or antisera against HO-1, ubiquitin (Ub), manganese superoxide dismutase (MnSOD), and α-synuclein or tyrosine hydroxylase (TH).


RESULTS
HMOX1 transfection induced cytoplasmic vacuolation and the accumulation of PAS+ inclusions in cultured astroglia. Numerous CA-like inclusions stained with PAS and immunoreactive for HO-1, Ub and MnSOD were observed in the brains of GFAP.HMOX1 mice, but were rarely encountered in age-matched, WT controls. Numbers of HO-1-positive CA were significantly increased in certain hippocampal strata of MCI subjects relative to NCI preparations. MnSOD and Ub proteins co-localized to CA in both the control and MCI specimens.


CONCLUSIONS
HO-1 promotes mitochondrial damage and CA biogenesis in astrocyte cultures and in the intact aging brain. CA formation is enhanced in the MCI hippocampus and thus occurs relatively early in the pathogenesis of AD. Glial HO-1 suppression may attenuate bioenergetic failure and slow disease progression in AD and other neurodegenerative conditions featuring accelerated accumulation of CA.
Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.
Wei
W
Song
Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada; Dept. of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
Hillel
H
Zukor
Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.
Adrienne
A
Liberman
Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.
Sagi
S
Kaduri
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Zoe
Z
Arvanitakis
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
David A
DA
Bennett
Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada; Dept. of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada. Electronic address: hyman.schipper@mcgill.ca.
Hyman M
HM
Schipper
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D051381:Rats
D006023:Glycoproteins; D008565:Membrane Proteins; D049452:Green Fluorescent Proteins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
Alzheimer disease; Astrocyte; Corpora amylacea; Heme oxygenase-1; Mild cognitive impairment; Mitochondria; Transgenic mice