Increased TNFalpha production and Cox-2 activity in organotypic brain slice cultures from APPsw transgenic mice.

beta-Amyloid (Abeta) peptides are the principal component of senile plaques and vascular deposits in Alzheimer's disease and are derived from the proteolytic cleavage of the beta-amyloid precursor protein (APP). We have previously shown that synthetic Abeta can stimulate cyclooxygenase-2 (Cox-2) activity in brain organotypic slice cultures. In the present study, we used brain slices from transgenic APP Swedish (TgAPPsw) mice and control littermates of different age groups to determine the effect of APP overexpression on the levels of prostaglandin and tumor necrosis factor alpha (TNFalpha) release. The production of eicosanoid and TNFalpha was increased as a function of age in organotypic brain slice culture from TgAPPsw mice compared to age matched control littermates. We also showed that the selective Cox-2 inhibitor NS-398 reduces the production of eicosanoid and TNFalpha in organotypic brain slice cultures of TgAPPsw mice. In conclusion, our data suggest that either activity or expression of Cox-2 is increased in TgAPPsw mice brains as a function of age, contributing to an increased production of pro-inflammatory eicosanoids and TNFalpha.