BETA-AMYLOID(25-35) PEPTIDE AND IFN-GAMMA SYNERGISTICALLY INDUCE THE PRODUCTION OF THE CHEMOTACTIC CYTOKINE MCP-1 JE IN MONOCYTES AND MICROGLIAL CELLS/

The molecular mechanisms involved in the development of senile plaques characteristic of aging and Alzheimer's disease are poorly understood . In this study, we examined whether human monocytes and murine microg lial cells stimulated with the active fragment of amyloid beta-protein (A beta(25-35)) express the monocyte chemotactic protein-1 (MCP-1)/JE . We show that upon incubation with A beta(25-35), human monocytes acc umulate MCP-1 mRNA and produce significant amounts of MCP-1,The effect of A beta(25-35) on MCP-1 secretion was neither mimicked by a scrambl ed analogue nor affected by polymyxin B sulfate, even though the latte r almost completely abolished the effect of LPS on MCP-1 expression. M urine microglial cells stimulated with A beta(25-35) also expressed hi gh levels of JE mRNA (the murine counterpart of MCP-1) and released bi oactive chemotactic factors, In addition, we report that IFN-gamma sig nificantly synergizes with A beta(25-35) either in human monocytes or in murine microglial cells, and that A beta(25-35) plus/minus IFN-gamm a-mediated early induction of MCP-1 mRNA does not require new protein synthesis, Finally, we provide evidence that the A beta(25-35)- and A beta plus IFN-gamma-induced production of MCP-1 is, in large part, med iated in an autocrine fashion by endogenous TNF-alpha. Taken together, our findings uncover another novel biologic action of A beta(25-35) a nd might help in better understanding the mechanisms underlying mononu clear phagocyte recruitment and activation into amyloid deposits.