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Journal of Neuroscience, Vol 12, 376-389, Copyright © 1992 by Society for Neuroscience
beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity
MP Mattson, B Cheng, D Davis, K Bryant, I Lieberburg and RE Rydel
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230.
In Alzheimer's disease (AD), abnormal accumulations of beta-amyloid are
present in the brain and degenerating neurons exhibit cytoskeletal
aberrations (neurofibrillary tangles). Roles for beta-amyloid in the
neuronal degeneration of AD have been suggested based on recent data
obtained in rodent studies demonstrating neurotoxic actions of beta-
amyloid. However, the cellular mechanism of action of beta-amyloid is
unknown, and there is no direct information concerning the biological
activity of beta-amyloid in human neurons. We now report on experiments in
human cerebral cortical cell cultures that tested the hypothesis that
beta-amyloid can destabilize neuronal calcium regulation and render neurons
more vulnerable to environmental stimuli that elevate intracellular calcium
levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino
acids 1-38 or 25-35 of the beta-amyloid protein enhanced glutamate
neurotoxicity in cortical cultures, while a peptide with a scrambled
sequence was without effect. beta APs alone had no effect on neuronal
survival during a 4 d exposure period. beta APs enhanced both kainate and
NMDA neurotoxicity, indicating that the effect was not specific for a
particular subtype of glutamate receptor. The effects of beta APs on
excitatory amino acid (EAA)-induced neuronal degeneration were
concentration dependent and required prolonged (days) exposures. The beta
APs also rendered neurons more vulnerable to calcium ionophore
neurotoxicity, indicating that beta APs compromised the ability of the
neurons to reduce intracellular calcium levels to normal limits. Direct
measurements of intracellular calcium levels demonstrated that beta APs
elevated rest levels of calcium and enhanced calcium responses to EAAs and
calcium ionophore. The neurotoxicity caused by EAAs and potentiated by beta
APs was dependent upon calcium influx since it did not occur in
calcium-deficient culture medium. Finally, the beta APs made neurons more
vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs
or calcium ionophore (i.e., increased staining with tau and ubiquitin
antibodies). Taken together, these data suggest that beta-amyloid
destabilizes neuronal calcium homeostasis and thereby renders neurons more
vulnerable to environmental insults.
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