Mitochondrial constituents of corpora amylacea and autofluorescent astrocytic inclusions in senescent human brain

Abstract

Corpora amylacea (CA) are cytoplasmic inclusions that accumulate in human brain in the course of normal aging, and to an even greater extent, in Alzheimer's disease and other neurodegenerative conditions. In senescent and Alzheimer-diseased human brains, astrocytes in limbic and periventricular regions exhibit red autofluorescent inclusions, homologous to Gomori-positive astrocyte granules previously described in the brains of aging rodents and other vertebrates. We have shown that Gomori inclusions in situ and in culture are derived from autophagocytosed mitochondria exhibiting iron-mediated peroxidase activity. In the human brain, the autofluorescent inclusions share many properties with CA. Both types of inclusion progressively accumulate in periventricular regions with advancing age, are largely astrocytic in origin, and contain various heat shock proteins and ubiquitin. Using histochemistry in conjunction with cofocal microscopy, we demonstrated that both CA and the red autofluorescent granules exhibit non-enzymatic peroxidase activity and an affinity for CAH and PAS. The only major divergent histochemical feature between the Gomori-positive astrocyte granules and CA is the presence of orange-red autofluorescence in the former and the absence of endogenous fluorescence in the latter. On the basis of numerous shared topographic and histochemical features, we hypothesized that CA are largely derived from autofluorescent (Gomori-positive) astrocyte granules which reside in periventricular regions of the senescent CNS. Immunofluorescent labeling and laser scanning confocal microscopy demonstrated consistent colocalization of the mitochondrial proteins, sulfite oxidase, and heat shock protein 60, to both CA and the autofluorescent astroglial inclusions. In addition, both CA and the autofluorescent astrocyte granules exhibit staining for DNA which colocalizes to mitochondrial antigens and therefore likely represents mitochondrial nucleic acid in dual-labeled preparations. These observations suggest that a) Gomori-positive astrocyte granules in human brain are homologous to those described in rodents, b) Gomori-positive granules may be structural precursors of CA in senescent human brain, and c) in the aging human brain, degenerate mitochondria within periventricular astrocytes give rise to autofluorescent cytoplasmic granules and corpora amylacea.

The Small Heat-shock Protein IbpB from Escherichia coli Stabilizes Stress-denatured Proteins for Subsequent Refolding by a Multichaperone Network

“…In eukaryotes, Hsp27, Hsp25, and ␣B-crystallines are found in protein granules of neurodegenerative diseases and after heat shock (33)(34)(35). In Drosophila, heat-induced granules dissolve after stress (36).…”

Suppression of Glial HO-1 Activitiy as a Potential Neurotherapeutic Intervention in AD

“…In young adult rats, subcutaneous CSH injections (150-300 mg/kg twice weekly for 3 weeks) induced 2-3 fold increases in numbers of peroxidase-positive astrocyte granules in the hippocampus, basal ganglia and other brain regions [24]. As in the case of the CSH-treated cultures, peroxidase-positive glial granules in the intact rat and human brain invariably exhibit mitochondrial epitopes in immunohistochemical preparations [19,25,26]. Further studies indicated that intracellular oxidative stress was likely responsible for the transformation of normal astrocyte mitochondria to peroxidase-positive inclusions in vitro and in the intact aging brain [5,[27][28][29].…”

Dietary supplementation with (R)-α-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex

“…In this regard, mitochondria may be particularly prone to iron deposition because of their involvement in heme and iron-sulfur synthesis. 10,11 The localization of iron to mitochondria may be highly undesirable as it may enhance the rate of mitochondrial decay and oxidant formation.…”