title: Amyloid-beta peptide induced inflammatory reaction is mediated by the cytokines tumor necrosis factor and interleukin-1.
abstract: A chronic inflammatory response possibly mediated by amyloid-beta (A beta) is believed to be a major factor in the pathology of Alzheimer's disease (AD). Recently, we demonstrated that in vivo administration of A beta produces an inflammatory response and vascular disruption as seen in the brains of AD patients. In an inflammatory response, leukocyte activation and extravasation involves cytokine production. Previous studies have indicated that immune interactions exist between the central nervous system and the peripheral immune mechanisms in AD. Increased levels of interleukin-1 beta (IL-1 beta) have been detected in brain tissue, cerebrospinal fluid, and blood/serum from AD patients. In addition, A beta stimulated the production of tumor necrosis factor-alpha (TNF-alpha) in brain astrocytes and murine monocytes. Using an animal model we investigated the role of the cytokines, TNF-alpha and IL-1 beta, in the A beta-induced inflammatory response. Adult male rats were perfused via an intra-aortic cannula with either A beta alone, interleukin-1 receptor antagonist (IL-1 ra) plus A beta, tumor necrosis factor-binding protein (TNF-bp) plus A beta or sterile saline. Serum analysis for TNF-alpha, IL-1 beta, A beta and NO showed a significant increase in TNF-alpha and A beta but not in IL-1 beta or NO after the injection of A beta. Control values for serum A beta averaged 1.6 ng/ml and in rats injected with A beta, 99.6% of this peptide was removed from the blood within 30 min. The mesenteric arterioles and venules were video recorded for 1-2 h and then processed for electron microscopy (EM). In rats given A beta alone there was extensive vascular disruption, including endothelial and smooth muscle damage with leukocyte adhesion and migration. Animals receiving either IL-1 ra or TNF-bp before A beta showed no in vivo leukocyte extravasation or vascular damage under EM. Therefore, the cytokines TNF-alpha and IL-1 beta seem to mediate the vascular disruption and inflammatory response initiated by A beta. Antagonism of these pro-inflammatory cytokines may offer new avenues for AD therapy.
authors.affiliation: Department of Physiology and Biophysics, College of Public Health, University of South Florida, Tampa 33612, USA. tsutton@com1.med.usf.edu
authors.forename: E T
authors.initials: ET
authors.lastname: Sutton
authors.forename: T
authors.initials: T
authors.lastname: Thomas
authors.forename: M W
authors.initials: MW
authors.lastname: Bryant
authors.forename: C S
authors.initials: CS
authors.lastname: Landon
authors.forename: C A
authors.initials: CA
authors.lastname: Newton
authors.forename: J A
authors.initials: JA
authors.lastname: Rhodin
mesh_terms: D016229:Amyloid beta-Peptides / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000097:blood / Q000276:immunology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D008854:Microscopy, Electron; D009569:Nitric Oxide / Q000276:immunology; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins / Q000276:immunology / Q000494:pharmacology; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C078592:amyloid beta-protein (1-40); C069521:recombinant human tumor necrosis factor-binding protein-1; D009569:Nitric Oxide