Amyloid beta and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia

Activated microglia surrounding amyloid beta-containing senile plaques synt hesize interleukin-l, an inflammatory cytokine that has been postulated to contribute to Alzheimer's disease pathology. Studies have demonstrated that amyloid beta treatment causes increased cytokine release in microglia and related cell cultures. The present work evaluates the specificity of this c ellular response by comparing the effects of amyloid beta to that of amylin , another amyloidotic peptide. Both lipopolysaccharide-treated THP-1 monocy tes and mouse microglia showed significant increases in mature interleukin- l beta release 48 h following amyloid beta or human amylin treatment, where as nonfibrillar rat amylin had no effect on interleukin-lp production by TH P-1 cells. Lipopolysaccharide-stimulated THP-1 cells treated with amyloid b eta or amylin also showed increased release of the proinflammatory cytokine s tumor necrosis factor-alpha and interleukin-6, as well as the chemokines interleukin-8 and macrophage inflammatory protein-1 alpha and -1 beta, THP- 1 cells incubated with fibrillar amyloid beta or amylin in the absence of l ipopolysaccharide also showed significant increases of both interleukin-1 b eta and tumor necrosis factor-alpha mRNA. Furthermore, treatment of THP-1 c ells with amyloid fibrils resulted in an elevated expression of the immedia te-early genes c-fos and junB. These studies provide further evidence that fibrillar amyloid peptides can induce signal transduction pathways that ini tiate an inflammatory response that is likely to contribute to Alzheimer's disease pathology.