Interaction of Alzheimer beta-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-alpha.
Immunological mechanisms, including stimulation of brain microglia and elevation of various inflammatory cytokines, have been implicated in the pathogenesis of Alzheimer's disease, where accumulation of beta-amyloid peptide (A beta) is one of its main pathological features. In this study we investigated the interaction of human monocyte-like cells with synthetic beta-amyloid peptide A beta (1-40) and its subfragment A beta (25-35). THP-1 cells (a transformed human monocyte cell line) were used with or without prior differentiation by phorbol myristate acetate (PMA), and cell activation was assessed by the secretion of tumor necrosis factor-alpha (TNF-alpha). First, it was shown that THP-1 cells could be induced to secrete significant amounts of TNF-alpha by interleukin-1, lipopolysaccharide, interferon-gamma (IFN-gamma) and PMA alone or in combination with each other. Next it was shown that A beta (1-40) could also induce secretion of TNF-alpha by THP-1 cells, but the effect was diminished when this peptide was applied in combination with IFN-gamma. The A beta subfragment A beta (25-35) was ineffective in inducing TNF-alpha production. The cellular action of A beta (1-40) appears to involve protein kinase C since pretreatment of THP-1 cells by PMA or the protein kinase C inhibitor H-7 diminished the cellular response to A beta (1-40). Identification of the pathway by which extracellular A beta activates the intracellular PKC-dependent secretion of TNF-alpha may help in developing new therapeutic strategies for Alzheimer's disease.
Klegeris
A
A
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada.
Walker
D G
DG
McGeer
P L
PL
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C074636:amyloid beta-protein (25-35); D007371:Interferon-gamma; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C