β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity

Mark P. Mattson, Bin Cheng, Dave Davis, Karin Bryant, Ivan Lieberburg, Russell E. Rydel

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)376-389
Number of pages14
JournalJournal of Neuroscience
Volume12
Issue number2
StatePublished - 1992
Externally publishedYes

Fingerprint

Amyloid
Homeostasis
Calcium
Neurons
Peptides
Calcium Ionophores
Neurofibrillary Tangles
Alzheimer Disease
Amyloidogenic Proteins
Excitatory Amino Acids
Aptitude
Kainic Acid
Glutamate Receptors
N-Methylaspartate
Ubiquitin
Culture Media
Glutamic Acid
Rodentia

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mattson, M. P., Cheng, B., Davis, D., Bryant, K., Lieberburg, I., & Rydel, R. E. (1992). β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. Journal of Neuroscience, 12(2), 376-389.

β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. / Mattson, Mark P.; Cheng, Bin; Davis, Dave; Bryant, Karin; Lieberburg, Ivan; Rydel, Russell E.

In: Journal of Neuroscience, Vol. 12, No. 2, 1992, p. 376-389.

Research output: Contribution to journalArticle

Mattson, MP, Cheng, B, Davis, D, Bryant, K, Lieberburg, I & Rydel, RE 1992, 'β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity', Journal of Neuroscience, vol. 12, no. 2, pp. 376-389.
Mattson, Mark P. ; Cheng, Bin ; Davis, Dave ; Bryant, Karin ; Lieberburg, Ivan ; Rydel, Russell E. / β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. In: Journal of Neuroscience. 1992 ; Vol. 12, No. 2. pp. 376-389.
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