Cysteamine (CSH; 2-mercaptoethylamine) stimulates the accumulation of peroxidase-positive inclusions in cultured astroglia akin to those observed in the aging periventricular brain. Because CSH induces the synthesis of a stress protein (heme oxygenase) in rat liver, we hypothesized that aspects of the cellular stress response may play a role in the biogenesis of CSH-induced astrocyte granules. In the present study, we performed indirect immunofluorescent staining and immunoblotting for various stress proteins in rat neuroglial cultures. Exposure of astrocyte cultures to CSH enhanced immunostaining for heme oxygenase-1 (HO-1) and heat-shock proteins 27, 72, and 90, but not glucose-regulated protein 94, relative to untreated cultures. CSH-pretreated astrocytes exhibited enhanced tolerance to H2O2 toxicity relative to untreated cells, providing physiological evidence of an antecedent stress response in the former. In addition, exposure for 12 days to H2O2, a known inducer of the stress response, elicited astrocyte granulation similar to that observed with CSH. Chronic induction of HO-1 and other stress proteins may participate in the biogenesis of metalloporphyrin-rich inclusions in CSH-treated astroglial cultures and in astrocytes of the aging periventricular brain.
Statin is a 57-kd nuclear protein expressed exclusively in nonproliferating cells. In the present study, immunohistochemical localization of statin in normal, senescent human brain revealed that virtually all neurons, ependymal cells, vascular smooth muscle cells, and endothelial cells are statin-positive and, hence, postmitotic. As we previously demonstrated in rodents, an unexpectedly large fraction of neuroglial cells throughout the aging human brain is statin-negative (range, 41 to 45%), consistent with the substantial retention of neuroglial proliferative capacity well into the senium. In Alzheimer's disease, there is a significant increase in the proportion of statin-negative neuroglia (range, 51 to 58%). In all regions except cerebellum, loss of statin in Alzheimer neuroglia could be accounted for by changes involving the astrocyte subpopulation. These results provide evidence that reactive gliosis in this neurodegenerative disorder encompasses some degree of astrocyte hyperplasia in addition to astrocyte hypertrophy. Maintenance of normal compartments of cycling and quiescent neuroglia in the senescent human brain may serve to define neurologic well-being during the aging process. Conversely, deviations in neuroglial cytokinetics may indicate the presence and extent of intervening neuropathologic processes.
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