The accumulation of amyloid ß (Aß)-peptides and their collection in fibrillar plaques in the human brain are believed to be responsible for Alzheimer's disease. The major neuron killers in the Alzheimer brain include proinflammatory cytokines and NO made by NOS-2 (inducible nitric oxide synthase-2). We have determined the effect of a soluble Aß peptide, Aß(1-40), on the expression of NOS-2 in astrocytes using a novel model system consisting of pure cultures of cells from adult human brains that, after the first three passages in vitro, become stably locked into the normal astrocytic phenotype like their counterparts in the adult human brain. Aß(1-40) alone stimulated quiescent astrocytes to start expressing functional NOS-2 and dumping NO into the culture medium during the next 4 days. But adding three of the proinflammatory cytokines commonly produced in the Alzheimer brain – IFN-gamma, IL-1ß, and TNF-alpha along with Aß(1-40) more than trebled NOS-2 expression and doubled NO production. In view of the possibility of myelin breakdown in the Alzheimer brain, we also tested the capability of myelin basic protein (MBP) to stimulate NO production using human astrocytes. We found that MBP mimicked the ability of Aß(1-40) to induce cells to release NO and adding the cytokine triad along with MBP more than doubled NO production and release. Thus, it appears that Aß peptides and MBP can join forces with proinflammatory cytokines to enhance the NO-mediated killing of neurons in the Alzheimer brain.
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