Age-related calcium changes, oxyradical damage, caspase activation and nuclear condensation in hippo campal neurons in response to glutamate and beta-amyloid

Neuronal degeneration increases with age in response to stressors, but the sub-cellular mechanism is unknown, partly because of previous difficulty in studying aged neurons in isolation. We studied the mechanism of enhanced neuronal susceptibility to glutamate and beta-amyloid in terms of condensed nuclei and other upstream events in hippocampal neurons cultured from old rats (24 months) compared to middle-age (10 months) and embryonic rats. Treatment of neurons from old animals with beta-amyloid (or glutamate) produced condensed nuclei 1.5 X (2 X) more frequently than middle-age and 3 X (4 X) more frequently than embryonic neurons. In addition to age-related baseline levels of caspase activation, neurons from old animals showed a 50% greater increase in caspase activation compared to middle-age and embryonic neurons. In contrast to glutamate treatment, beta-amyloid caused oxyradical damage as protein carbonyls increased 2-fold higher for old neurons than middle-age and 10-fold higher than embryonic neurons. Contrary to expectations, steady-state calcium levels for adult neurons did not increase in response to beta-amyloid. Overall, these results suggest that aged neurons have an inherent increased susceptibility to beta-amyloid toxicity through an early action of oxyradicals followed by caspase activation and nuclear condensation, a common pathway of apoptosis. Age-related glutamate toxicity involves other steps that lead to nuclear condensation, but neuron responses to calcium influx appear more important to cell death than the amount of influx. (c) 2005 Elsevier Inc. All rights reserved.