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

Abstract

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 19 month-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 suoperoxide dismutase (MnSOD), 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, wild-type 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.

Exploring the elusive composition of corpora amylacea of human brain

“…A more recent article 47 suggests that the biogenesis of CA can be envisioned in the context of a revised free radical-mitochondrial-metal theory of CNS ageing, in which sustained up-regulation of the stress protein heme oxygenase-1 in astrocytes may play a pivotal role. Up-regulation of heme oxygenase-1 can lead to the release of intracellular iron and carbon monoxide, thereby promoting the transformation of normal mitochondria into Gomori granules and CA 8 . It must be pointed out that although immunohistochemical evidence in those studies may be subject to the concerns raised in the present work, mitochondrial remnants within CA have been widely demonstrated in ultrastructural studies.…”

Misfolded SOD1 is not a primary component of sporadic ALS

“…Moreover, some of this putative immunoreactive signal resembles corpora amylacea structures, glycoproteinacous inclusions frequently found in the CNS tissues of elderly people [10, 38, 52], including both non-neurological control and SALS patients [4]. Such structures have been reported to immunostain for multiple proteins including ubiquitin, heme oxygenase, Mn SOD1, and alpha-synuclein [62], and do not represent disease-specific pathology.…”

Heme Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce Neurodegeneration?

“…Indeed, transferrin receptor-independent accumulation of iron and mitochondrial electron transport (complex I) deficits may be promoted by the enhanced glial HO-1 activity [115,116,117,118]. In addition, the redox-active glial iron mediates bioactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the dopaminergic toxin 1-methyl-4-phenylpyridine (MPP + ), despite the inactivation of monoamine oxidases [119] and that the selective overexpression of HO-1 in astrocytes of transgenic mice induces parkinsonian features [120].…”