TY - JOUR
T1 - β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity
AU - Mattson, Mark P.
AU - Cheng, Bin
AU - Davis, Dave
AU - Bryant, Karin
AU - Lieberburg, Ivan
AU - Rydel, Russell E.
PY - 1992
Y1 - 1992
N2 - In Alzheimer's disease (AD), abnormal accumulations of β-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for β-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of β-amyloid. However, the cellular mechanism of action of β-amyloid is unknown, and there is no direct information concerning the biological activity of β-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that β-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic β-amyloid peptides (βAPs) corresponding to amino acids 1-38 or 25-35 of the β-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. βAPs alone had no effect on neuronal survival during a 4 d exposure period. βAPs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of βAPs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The βAPs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that βAPs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that βAPs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by βAPs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the βAPs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., in- creased staining with tau and ubiquitin antibodies). Taken together, these data suggest that β-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.
AB - In Alzheimer's disease (AD), abnormal accumulations of β-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for β-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of β-amyloid. However, the cellular mechanism of action of β-amyloid is unknown, and there is no direct information concerning the biological activity of β-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that β-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic β-amyloid peptides (βAPs) corresponding to amino acids 1-38 or 25-35 of the β-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. βAPs alone had no effect on neuronal survival during a 4 d exposure period. βAPs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of βAPs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The βAPs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that βAPs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that βAPs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by βAPs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the βAPs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., in- creased staining with tau and ubiquitin antibodies). Taken together, these data suggest that β-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.
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M3 - Article
C2 - 1346802
AN - SCOPUS:0026570528
SN - 0270-6474
VL - 12
SP - 376
EP - 389
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 2
ER -