Age-related calcium changes, oxyradical damage, caspase activation and nuclear condensation in hippocampal 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 1.5x (2x) more frequently than middle-age and 3x (4x) 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.
Brewer
Gregory J
GJ
Medical Microbiology and Immunology, Southern Illinois University School of Medicine, P.O. Box 19626, Springfield, IL 62794-9626, USA. gbrewer@siumed.edu
Lim
A
A
Capps
Nicole G
NG
Torricelli
John R
JR
D000375:Aging / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002467:Cell Nucleus; D002478:Cells, Cultured; D004792:Enzyme Precursors / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004792:Enzyme Precursors; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium