Elsevier

Brain Research

Volume 621, Issue 1, 3 September 1993, Pages 35-49
Brain Research

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

https://doi.org/10.1016/0006-8993(93)90295-XGet rights and content

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.

References (69)

  • GlennerG.G. et al.

    Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein

    Biochem. Biophys. Res. Commun.

    (1984)
  • GreenamyreJ.T. et al.

    Excitatory amino acids and Alzheimer's disease

    Neurobiol. Aging

    (1989)
  • HeftiF. et al.

    Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases

    Neurobiol. Aging

    (1989)
  • HilbichC. et al.

    Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer's disease

    J. Mol. Biol.

    (1991)
  • JoslinG. et al.

    Substance P, bombesin and the amyloid β-protein compete with α11AT antitrypsin-protease complexes for binding to the serpin-enzyme complex (SEC) receptors

    J. Biol. Chem.

    (1991)
  • KohJ.-Y. et al.

    β-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage

    Brain Res.

    (1990)
  • MattsonM.P.

    Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and calcium influx in cultured hippocampal neurons

    Neuron

    (1990)
  • MattsonM.P.

    Calcium as sculptor and destroyer of neural circuitry

    Exp. Gerontol.

    (1992)
  • MattsonM.P. et al.

    Glia protect hippocampal neurons against excitatory amino acid-induced degeneration: involvement of fibroblast growth factor

    Int. J. Dev. Neurosci.

    (1990)
  • MattsonM.P. et al.

    Developmental expression, compartmentalization, and possible role in excitotoxicity of a putative NMDA receptor protein in cultured hippocampal neurons

    Brain Res.

    (1991)
  • MattsonM.P. et al.

    Evidence for calcium-reducing and excitoprotective roles for the calcium-binding protein calbindin-D28k in cultured hippocampal neurons

    Neuron

    (1991)
  • MattsonM.P. et al.

    Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of β-amyloid precursor protein

    Neuron

    (1993)
  • MitsuhashiM. et al.

    Amyloid β protein substituent peptides do not interact with the substance P receptor expressed in cultured cells

    Mol. Brain Res.

    (1991)
  • OltersdorfT. et al.

    The Alzheimer amyloid precursor protein

    J. Biol. Chem.

    (1990)
  • PhillipsH.S. et al.

    BDNF mRNA is decreased in the hippocampus of individuals with Alzheimers disease

    Neuron

    (1991)
  • PikeC.J. et al.

    In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity

    Brain Res.

    (1991)
  • QuonD. et al.

    Fibroblast growth factor induces beta-amyloid precursor mRNA in glial but not neuronal cultured cells

    Biochem. Biophys. Res. Commun.

    (1990)
  • UchidaY. et al.

    The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein

    Neuron

    (1991)
  • YayonA. et al.

    Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor

    Cell

    (1991)
  • AndersonK.J. et al.

    Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo

    Nature

    (1988)
  • ArispeN. et al.

    Alzheimer's disease amyloid β protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum

  • BarrowC.J. et al.

    Solution structures of β peptide and its constituent fragments: relation to amyloid deposition

    Science

    (1991)
  • BaskinF. et al.

    Release of a putative 60-kDa amyloidogenic Alzheimer amyloid precursor protein from PC-12 cells, and the isolation of AD-fibroblast hybrids

  • ChengB. et al.

    IGF-I and IGF-II protect cultured hippocampal and septal neurons against calcium-mediated hypoglycemic damage

    J. Neurosci.

    (1992)
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