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Effects of the carboxyl‐terminal fragment of Alzheimer's amyloid precursor protein and amyloid β ‐peptide on the production of cytokines and nitric oxide in glial cells

In a brain with Alzheimer's disease (AD), activated glial cells are observed surrounding amyloid plaque. In this study, to investigate the roles of carboxyl‐terminal fragments (CTs) of amyloid precursor protein (APP) and amyloid β‐peptide (Aβ) in inflammatory processes possibly linked to neurodegeneration associated with AD, we examined the effects of the CT of APP with 105 amino acid residues (CT105) on the alteration of inflammatory mediators in rat cortical astrocytes and microglial cells and compared these effects to those of Aβ. We found that cytokines including interleukin 1β (IL‐1β) and tumor necrosis factor a and chemokines such as macrophage inflammatory protein 1a, monocyte chemoattractant protein 1, and RANTES (regulated on activation, normal T expressed and secreted) were highly induced by 100 nM CT105 in a time‐dependent manner, whereas the same amount of Aβ1‐42 did not significantly induce these mediators. In addition, inducible nitric oxide synthase (iNOS) expression and nitrite accumulation induced by CT105 were inhibited by IL‐1 receptor antagonist (IL‐1ra). Furthermore, the addition of conditioned media from CT105‐treated astrocytes to rat cortical neurons caused a decrease in cell viability. Pretreatment with IL‐1ra, NG‐nitro‐L‐arginine methyl ester (a specific inhibitor of NOS), and pyrollidine dithiocarbamate [an inhibitor of nuclear factor‐κB (NF‐κB)] prevented neuronal cell death caused by conditioned media from CT105‐ treated astrocytes. Our results indicate that the activation of astrocytes by CT105 leads to neuronal cell death in vitro, presumably caused by the increase in nitric oxide derived from the induction of iNOS through the activation of cytokines and NF‐κB. Thus, CT105 may contribute to stimulation of inflammatory processes linked to delayed neurodegeneration in AD.