Amyloid β-peptide stimulates nitric oxide production in astrocytes through an NFκB-dependent mechanism

The major pathological features of Alzheimer's disease (AD) include amyloid plaques composed primarily of the beta-amyloid (A beta) peptide, degenerating neurons and neurofibrillary tangles, and the presence of numerous activated astrocytes and microglia, Although extensive genetic data implicate A beta in the neurodegenerative cascade of AD, the molecular mechanisms underlying its effects on neurons and glia and the relationship between glial activation and neuronal death are not well defined. A beta has been shown to induce glial activation, and a growing body of evidence suggests that activated glia contribute to neurotoxicity through generation of inflammatory cytokines and neurotoxic free radicals, such as nitric oxide (NO), potent sources of oxidative stress known to occur in AD. It is therefore crucial to identify specific A beta-induced molecular pathways mediating these responses in activated glia, We report that A beta stimulates the activation of the transcription factor NF kappa B in rat astrocytes, that NF kappa B activation occurs selectively from p65 transactivation domain 2, and that A beta-induced NO synthase expression and NO production occur through an NF kappa B-dependent mechanism. This demonstration of how AP couples an intracellular signal transduction pathway involving NF kappa B to a potentially neurotoxic response provides a key mechanistic link between A beta and the generation of oxidative damage. Our results also suggest possible molecular targets upon which to focus future drug discovery efforts for AD.