Secreted beta-amyloid precursor protein activates microglia via JNK and p38-MAPK.
Reactive microglia are thought to play a role in the pathogenesis of Alzheimer's disease (AD) and are localized to the senile plaques that are associated with cognitive decline. The beta-amyloid precursor protein (betaAPP) is over-expressed in the dystrophic neurites near such plaques, and secreted forms of betaAPP (sAPPalpha) activate inflammatory responses in microglia. To characterize the mechanisms by which sAPPalpha activates microglia, we assayed its effects on MAP kinases, including c-Jun N-terminal kinases (JNK), extracellular signal-regulated protein kinases (ERK), and p38-MAPK. sAPPalpha was found to rapidly activate JNKs, ERKs and p38-MAPK in a dose-dependent manner. The JNK inhibitor SP600125 and the p38 inhibitor SB203580 independently reduced both nitrite accumulation and induction of inflammatory nitric oxide synthase (iNOS). By contrast, inhibition of the ERK pathway with U0126 did not appreciably affect either outcome measure. These findings suggest that sAPP activates the ERK, JNK and p38 classes of MAP kinases but that only JNK and p38-MAPK are critical for activation of microglia by sAPPalpha, a process that compromises neuronal function and survival.
Bodles
Angela M
AM
Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Barger
Steven W
SW
D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D000873:Anthracenes; D002070:Butadienes; D004338:Drug Combinations; D007093:Imidazoles; D009570:Nitriles; D009573:Nitrites; D011725:Pyridines; C113580:U 0126; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580