ERK pathway activation is required for amyloid-β(1-40)(-)induced neurotoxicity of THP-1 human monocytes towards SK-N-SH neuroblastoma.
Alzheimer's disease (AD) is characterized by amyloid-β peptide deposition, increased activated microglia, and progressive loss of neurons in the brain. Although Aβ₁₋₄₀ can elicit inflammation in microglia, the intracellular signaling events mediating these effects are poorly defined. Here we show that cell-free supernatant from Aβ₁₋₄₀-treated THP-1 monocytes induced cytotoxicity towards neuroblastoma SK-N-SH cells. Exposure of THP-1 monocytes to Aβ₁₋₄₀ leads to increased tyrosine phosphorylation and extracellular signaling-regulated kinase (ERK) and increased levels of inflammatory cytokines (IL-1β, IL-8, and TNF-α) in the supernatant of THP-1 monocytes. Pretreatment of THP-1 monocytes with either a protein tyrosine kinase (PTK) inhibitor or an ERK inhibitor protects SK-N-SH cells from the cytotoxic effect of conditional supernatant from Aβ₁₋₄₀-treated THP-1 monocytes. Aβ₁₋₄₀-treated THP-1 monocytes also lead to upregulation of cyclooxygenase-2 and iNOS expression and increased of nitric oxide production. These results suggest that Aβ₁₋₄₀-induced activation of PTK/MEK/ERK pathway in THP-1 monocytes leads to the release of inflammatory factors that are toxic to SK-N-SH cells and might contribute to the onset of AD.
Department of Pharmacology, Xuan-wu Hospital of Capital Medical University, Education Ministry Key Laboratory for Neurodegenerative Disease, 45 Chang-chun Street, Beijing, 100053, PR China.
Lin-Lin
LL
Yin
Wei
W
Li
Yan-Qi
YQ
Chu
Lin
L
Li
D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D046529:Microscopy, Electron, Transmission; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D048049:Extracellular Signal-Regulated MAP Kinases