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Role of Cyclic GMP in the Regulation of Neuronal Calcium and Survival by Secreted Forms of β‐Amyloid Precursor
Author(s) -
Barger Steven W.,
Fiscus Ronald R.,
Ruth Peter,
Hofmann Franz,
Mattson Mark P.
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.64052087.x
Subject(s) - glutamate receptor , protein kinase a , neuroprotection , neurotoxicity , chemistry , nmda receptor , pde10a , cyclic nucleotide , calcium , kinase , medicine , endocrinology , biochemistry , microbiology and biotechnology , biology , pharmacology , toxicity , receptor , nucleotide , enzyme , phosphodiesterase , gene
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 ([Ca 2+ ] i ). We have investigated the mechanism through which APP s s exert these effects on cultured hippocampal neurons. The ability of APP s s to lower rapidly [Ca 2+ ] 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 [Ca 2+ ] 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 [Ca 2+ ] i ‐lowering and excitoprotective effects on target neurons through increases in cGMP levels.