Calcium-destabilizing and neurodegenerative effects of aggregated β-amyloid peptide are attenuated by basic FGF

Mark P. Mattson, Kevin J. Tomaselli, Russell E. Rydel

Research output: Contribution to journalArticle

Abstract

The mechanisms that contribute to neuronal degeneration in Alzheimer's disease (AD) are not understood. Abnormal accumulations of β-amyloid peptide (βAP) are thought to be involved in the neurodegenerative process, and recent studies have demonstrated neurotoxic actions of βAPs. We now report that the mechanism of βAP-mediated neurotoxicity in hippocampal cell culture involves a destabilization of neuronal calcium homeostasis resulting in elevations in intracellular calcium levels ([Ca2+]i) that occur during exposure periods of 6 hr to several days. Both the elevations of [Ca2+]i and neurotoxicity were directly correlated with aggregation of the peptide as assessed by βAP immunoreactivity and confocal laser scanning microscopy. Exposure of neurons to βAP resulted in increased sensitivity to the [Ca2+]i-elevating and neurodegenerative effects of excitatory amino acids. Moreover, [Ca2+]i responses to membrane depolarization and calcium ionophore were greatly enhanced in βAP-treated neurons. Neurons in low cell density cultures were more vulnerable to βAP toxicity than were neurons in high cell density cultures. Basic fibroblast growth factor (bFGF), but not nerve growth factor (NGF), significantly reduced both the loss of calcium homeostasis and the neuronal damage otherwise caused by βAP. In AD, βAP may endanger neurons by destabilizing calcium homeostasis and bFGF may protect neurons by stabilizing intracellular calcium levels. Aggregation of βAP seems to be a major determinant of its [Ca2+]i-destabilizing and neurotoxic potency.

Original languageEnglish (US)
Pages (from-to)35-49
Number of pages15
JournalBrain Research
Volume621
Issue number1
DOIs
StatePublished - Sep 3 1993
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Fura-2
  • Glutamate
  • Hippocampus
  • Nerve growth factor
  • Neurotoxicity

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology
  • Clinical Neurology
  • Neuroscience(all)

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