Synergistic Induction of Nitric Oxide by β-Amyloid and Cytokines in Astrocytes

Abstract The deposition of β-amyloid peptides in the brain in form of senile plaque is the key event responsible for Alzheimer pathology. Among various mechanisms that have been proposed to explain the neurotoxicity of β-amyloid deposits, a new one, recently identified in our laboratory, suggests that β-amyloid peptides may be indirectly toxic for neurons by activating microglial cells to produce NO (2). We have investigated if astrocytes, nerve cells that play an important role in many brain diseases, also might be involved in a similar mechanism of neuronal damage. The results have demonstrated that (1) β-amyloid peptide (25-35), in the presence of IFNγ or TNFα, induces the production of NO in the astrocyte cell line C6, while neither cytokine was effective per se; (2) NO generation is also synergically induced by β-amyloid peptide (25-35) in the presence of IL-1β, the latter being a cytokine able to activate astrocytes per se; (3) the effect of β-amyloid peptide (25-35) is due to the induction of the expression of the gene of inducible NO-synthase. These findings suggest that astrocytes, activated by deposited β-amyloid peptides and cytokines, may play a role in neuronal damage via the indirect NO mechanism.