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The mechanisms by which aluminum interacts with the nervous system are only partly understood. In this study, we used cultured astrocytes and neurons to investigate the effects of long exposures to aluminum (1 mM). We found that aluminum accumulated both in neurons and astrocytes. After 8-12 days exposure, aluminum caused strong changes in the morphology of astrocytes including shrinkage of cell bodies and retraction of processes. Exposures over 15-18 days reduced astrocytes viability by 50%. Aluminum-induced degeneration of astrocytes involved the DNA fragmentation characteristic of apoptosis, and staining of aluminum-treated astrocytes with the DNA-binding fluorochrome Hoeschst 33258 revealed the typical apoptotic condensation and fragmentation of chromatin. Aluminum was also found to be neurotoxic, causing first (4-6 days) abnormal clustering and aggregation, and later (8-12 days) neuronal death. Interestingly, aluminum neurotoxicity occurred in neuroglial cultures containing approximately 10% astrocytes but not in near-pure neuronal cultures containing only 1% astrocytes. Staining of co-cultured cells with Hoeschst 33258 showed apoptotic condensation and fragmentation of chromatin in aluminum-treated astrocytes but not in co-cultured neurons. Our study demonstrates that aluminum can induce the apoptotic degeneration of astrocytes, and that this toxicity is critical in determining neuronal degeneration and death. Aluminum-mediated apoptosis of cultured astrocytes may be also a valuable model system to study the mechanisms underlying apoptosis in glial cells., (Copyright 1999 Elsevier Science B.V.)