MITOCHONDRIAL CONSTITUENTS OF CORPORA-AMYLACEA AND AUTOFLUORESCENT ASTROCYTIC INCLUSIONS IN SENESCENT HUMAN BRAIN

Corpora amylacea (CA) are cytoplasmic inclusions that accumulate in hu man brain in the course of normal aging, and to an even greater extent , in Alzheimer's disease and other neurodegenerative conditions. In se nescent and Alzheimer-diseased human brains, astrocytes in limbic and periventricular regions exhibit red autofluorescent inclusions, homolo gous to Gomori-positive astrocyte granules previously described in the brains of aging rodents and other vertebrates. We have shown that Gom ori inclusions in situ and in culture are derived from autophagocytose d mitochondria exhibiting iron-mediated peroxidase activity. In the hu man brain, the autofluorescent inclusions share many properties with C A. Both types of inclusion progressively accumulate in periventricular regions with advancing age, are largely astrocytic in origin, and con tain various heat shock proteins and ubiquitin. Using histochemistry i n conjunction with confocal microscopy, we demonstrated that both CA a nd the red autofluorescent granules exhibit non-enzymatic peroxidase a ctivity and an affinity for CAH and PAS. The only major divergent hist ochemical feature between the Gomori-positive astrocyte granules and C A is the presence of orange-red autofluorescence in the former and the absence of endogenous fluorescence in the latter. On the basis of num erous shared topographic and histochemical features, we hypothesized t hat CA are largely derived from autofluorescent (Gomori-positive) astr ocyte granules which reside in periventricular regions of the senescen t CNS. Immunofluorescent labeling and laser scanning confocal microsco py demonstrated consistent colocalization of the mitochondrial protein s, sulfite oxidase, and heat shock protein 60, to both CA and the auto fluorescent astroglial inclusions. In addition, both CA and the autofl uorescent astrocyte granules exhibit staining for DNA which colocalize s to mitochondrial antigens and therefore likely represents mitochondr ial nucleic acid in dual-labeled preparations. These observations sugg est that a) Gomori-positive astrocyte granules in human brain are homo logous 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 ast rocytes give rise to autofluorescent cytoplasmic granules and corpora amylacea. (C) 1995 Wiley-Liss, Inc.