One of the earliest signs of age-related macular degeneration (AMD) is the formation of drusen which are extracellular deposits beneath the retinal pigmented epithelium (RPE). To investigate the relationship between drusen and AMD, we focused on amyloid beta (Abeta), a major component of drusen and also of senile plaques in the brain of Alzheimer's patients. We previously reported that Abeta was accumulated in drusen-like structure in senescent neprilysin gene-disrupted mice. The purpose of this study was to investigate the influence of Abeta on factor B, the main activator of the complement alternative pathway. The results showed that Abeta did not directly modulate factor B expression in RPE cells, but increased the production of monocyte chemoattractant protein-1 (MCP-1). Abeta also increased the production of IL-1beta and TNF-alpha in macrophages/microglia, and exposure of RPE cells to IL-1beta and TNF-alpha significantly up-regulated factor B. Co-cultures of RPE cells and macrophages/microglia in the presence of Abeta significantly increased the expression of factor B in RPE. These findings indicate that cytokines produced by macrophages/microglia that were recruited by MCP-1 produced in RPE cells stimulated by Abeta up-regulate factor B in RPE cells. Thus, a combined mechanism exists for Abeta-induced for the activation of the complement alternative pathway in the subretinal space; cytokine-induced up-regulation of activator factor B and dysfunction of the inhibitor factor I by direct binding to Abeta as suggested in our earlier study.