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 language | English (US) |
---|---|
Pages (from-to) | 2087-2096 |
Number of pages | 10 |
Journal | Journal of Neurochemistry |
Volume | 64 |
Issue number | 5 |
State | Published - 1995 |
Externally published | Yes |
Keywords
- β-Amyloid precursor proteins
- Alzheimer's disease
- Cyclic GMP
- Neuronal calcium
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience