Secreted β-amyloid precursor protein activates microglia via JNK and p38-MAPK

• Published in: Neurobiology of aging 2005, Vol.26 (1), p.9-16
• Main Authors: Bodles, Angela M., Barger, Steven W.
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid beta-Protein Precursor - pharmacology; Animals; Animals, Newborn; Anthracenes - pharmacology; APP; Biological and medical sciences; Blotting, Western - methods; Butadienes - pharmacology; Cells, Cultured; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; Drug Combinations; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Imidazoles - pharmacology; Inflammation; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; MAP kinase; Medical sciences; Microglia; Microglia - drug effects; Neurology; Nitric oxide synthase; Nitriles - pharmacology; Nitrites - metabolism; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pyridines - pharmacology; Rats; Stress-activated kinase; Time Factors
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2004.02.022

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 β-amyloid precursor protein (βAPP) is over-expressed in the dystrophic neurites near such plaques, and secreted forms of βAPP (sAPPα) activate inflammatory responses in microglia. To characterize the mechanisms by which sAPPα 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. sAPPα 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 sAPPα, a process that compromises neuronal function and survival.