Beta-amyloid activates the O2- forming NADPH oxidase in microglia, monocytes and neutrophils.

The deposition of b-amyloid in the brain is the key pathogenetic event in Alzheimer’s disease. Among the various mechanisms proposed to explain the neurotoxicity of b-amyloid deposits, a new one, recently identified in our and other laboratories, suggests that b-amyloid is indirectly neurotoxic by activating microglia to produce toxic inflammatory mediators such as cytokines, nitric oxide, and oxygen free radicals. Three findings presented here support this mechanism, showing that b-amyloid peptides (25–35), (1–39), and (1–42) activated the classical NADPH oxidase in rat primary culture of microglial cells and human phagocytes: 1) The exposure of the cells to b-amyloid peptides stimulates the production of reactive oxygen intermediates; 2) the stimulation is associated with the assembly of the cytosolic components of NADPH oxidase on the plasma membrane, the process that corresponds to the activation of the enzyme; 3) neutrophils and monocytes of chronic granulomatous disease patients do not respond to b-amyloid peptides with the stimulation of reactive oxygen intermediate production. Data are also presented that the activation of NADPH oxidase requires that b-amyloid peptides be in fibrillary state, is inhibited by inhibitors of tyrosine kinases or phosphatidylinositol 3-kinase and by dibutyryl cyclic AMP, and is potentiated by interferon-g or tumor necrosis factor-a.