Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of β-amyloid precursor

S. W. Barger, R. R. Fiscus, P. Ruth, F. Hofmann, M. P. Mattson

Research output: Contribution to journalArticle

Abstract

The Alzheimer's disease (AD) β-amyloid precursor proteins (βAPPs) are large membrane-spanning proteins that give rise to the βA4 peptide deposited in AD amyloid plaques. βAPPs can also yield soluble forms (APP(s)s) that are potently neuroprotective against glucose deprivation and glutamate toxicity, perhaps through their ability to lower the intraneuronal calcium concentration ([Ca2+](i)). We have investigated the mechanism through which APP's exert these effects on cultured hippocampal neurons. The ability of APP(s)s to lower rapidly [Ca2+](i) was mimicked by membrane-permeable analogues of cyclic AMP (cAMP) and cyclic GMP (cGMP), as well as agents that elevate endogenous levels of these cyclic nucleotides. However, only cGMP content was increased by APP(s) treatment, and specific inhibition of cGMP- dependent protein kinase (but not cAMP-dependent kinase) blocked the activity of APP(s)s. A membrane-permeable analogue of CGMP (8-bromo-cGMP) also mimicked the ability of APP(s)s to attenuate the elevation of [Ca2+](i) by glutamate, apparently through inhibition of NMDA receptor activity. In addition, 8-bromo-cGMP afforded protection against glucose deprivation and glutamate toxicity, and the protection by APP(s)S against glucose deprivation was blocked by an inhibitor of cGMP-dependent kinase. Together, these data suggest that APP(s)s mediate their [Ca2+](i)-lowering and excitoprotective effects on target neurons through increases in cGMP levels.

Original languageEnglish (US)
Pages (from-to)2087-2096
Number of pages10
JournalJournal of Neurochemistry
Volume64
Issue number5
StatePublished - 1995
Externally publishedYes

Fingerprint

Amyloid beta-Protein Precursor
Cyclic GMP
Amyloid
Calcium
Aptitude
Glutamic Acid
Glucose
Cyclic AMP
Membranes
Alzheimer Disease
Neurons
Toxicity
Guanylate Kinases
Phosphotransferases
Cyclic GMP-Dependent Protein Kinases
Adenylate Kinase
Cyclic Nucleotides
Protein S
Amyloid Plaques
N-Methyl-D-Aspartate Receptors

Keywords

  • β-Amyloid precursor proteins
  • Alzheimer's disease
  • Cyclic GMP
  • Neuronal calcium

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Barger, S. W., Fiscus, R. R., Ruth, P., Hofmann, F., & Mattson, M. P. (1995). Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of β-amyloid precursor. Journal of Neurochemistry, 64(5), 2087-2096.

Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of β-amyloid precursor. / Barger, S. W.; Fiscus, R. R.; Ruth, P.; Hofmann, F.; Mattson, M. P.

In: Journal of Neurochemistry, Vol. 64, No. 5, 1995, p. 2087-2096.

Research output: Contribution to journalArticle

Barger, SW, Fiscus, RR, Ruth, P, Hofmann, F & Mattson, MP 1995, 'Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of β-amyloid precursor', Journal of Neurochemistry, vol. 64, no. 5, pp. 2087-2096.
Barger, S. W. ; Fiscus, R. R. ; Ruth, P. ; Hofmann, F. ; Mattson, M. P. / Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of β-amyloid precursor. In: Journal of Neurochemistry. 1995 ; Vol. 64, No. 5. pp. 2087-2096.
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