Astroglial heme oxygenase-1 and the origin of corpora amylacea in aging and degenerating neural tissues

• Published in: Experimental neurology Vol. 254; pp. 78 - 89
• Main Authors: Song, Wei, Zukor, Hillel, Liberman, Adrienne, Kaduri, Sagi, Arvanitakis, Zoe, Bennett, David A., Schipper, Hyman M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.04.2014; Elsevier
• Subjects: Adult and adolescent clinical studies; Aged; Aged, 80 and over; Aging - metabolism; Aging - pathology; Alzheimer disease; Animals; Animals, Newborn; Astrocyte; Astrocytes - cytology; Astrocytes - enzymology; Astrocytes - pathology; Biological and medical sciences; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Corpora amylacea; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development. Senescence. Regeneration. Transplantation; Female; Fundamental and applied biological sciences. Psychology; Geriatrics; Glycoproteins - metabolism; Green Fluorescent Proteins - genetics; Heme oxygenase-1; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hippocampus - enzymology; Hippocampus - pathology; Humans; Inclusion Bodies - enzymology; Inclusion Bodies - pathology; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Mild cognitive impairment; Mitochondria; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurology; Organic mental disorders. Neuropsychology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Transgenic mice; Vertebrates: nervous system and sense organs; Corpora amylacea; Mitochondria; Alzheimer disease; Mild cognitive impairment; Heme oxygenase-1; Transgenic mice; Astrocyte; Amyloid body; Nervous system diseases; Senescence; Cognitive disorder; Enzyme; Neuroglia; Rodentia; Cerebral disorder; Oxygenase; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Degenerative disease; mild cognitive impairment; Oxidoreductases; Nervous tissue
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2014.01.006

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. 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). 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. 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. •HMOX1 transfection promotes corpora amylacea (CA) biogenesis in rat astrocytes.•CA formation is accelerated in the brains of aging GFAP.HMOX1 mice.•CA biogenesis is augmented in mild cognitive impairment, a prodromal stage of AD.•Glial HO-1 suppression may confer neuroprotection in Alzheimer disease.