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.