Amyloid β and Amylin Fibrils Induce Increases in Proinflammatory Cytokine and Chemokine Production by THP‐1 Cells and Murine Microglia

Abstract

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

Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid β-peptide-induced cholinergic dysfunction

“…Control animals were infused with the nontoxic reverse fragment Ab40-1. Accumulation of Ab in the hippocampus was demonstrated immunohistochemially with anti-Ab (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) antibodies, but no Congo red birefringence was observed. 21 AG (100 mg/kg, i.p.)…”

“…[1][2][3][4][5][6][7] It has been demonstrated that aggregation of Ab can attract inflammatory mediators 8,9 which, in turn, generate NO radicals. 10 We have previously demonstrated that continuous intracerebroventricular infusion of Ab induced a time-dependent expression of iNOS in the hippocampus and that treatment with specific inhibitors for iNOS ameliorated Ab-induced impairment of nicotine-evoked ACh release and spatial memory deficits.…”

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…Activation of microglia results in the production of NO, oxygen free radicals, proteases, adhesion molecules and proinflammatory cytokines such as TNFα, IL-1β, LT-α, and IL-6 [27][28][29][30][31]. It is thought that the overproduction of these inflammatory mediators is important in the degenerative process in patients with AD [32].…”

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

“…AD has a significant inflammatory component evidenced by abundant plaque-associated microglia that exhibit a reactive phenotype (Akiyama and McGeer, 1990;Masliah et al, 1991;Peress et al, 1993;Akiyama et al, 2000). The activated microglia release a diverse array of proinflammatory molecules that act to exacerbate the disease process and contribute to neuronal death (Combs et al, 2000(Combs et al, , 2001bYates et al, 2000).…”