title: Molecular mechanisms underlying cyclic AMP inhibition of macrophage dependent TNF-alpha production and neurotoxicity in response to amyloidogenic C-terminal fragment of Alzheimer's amyloid precursor protein.
abstract: In the present study, we characterized the intracellular pathway involved in the macrophage production of tumor necrosis factor-alpha (TNF-alpha) and the molecular mechanisms by which cyclic AMP (cAMP) regulates the neurotoxic inflammatory signaling cascade in response to the 105 amino acid carboxyl-terminal fragment (CT105) of amyloid precursor protein, a candidate of alternative toxic elements in Alzheimer's disease (AD) pathology. CT105 in combination with interferon-gamma (IFN-gamma) elicited a robust and sustained increase of TNF-alpha production due to enhanced TNF-alpha mRNA transcription, mediated via increased nuclear factor-kappaB (NF-kappaB) in human macrophages derived from monocytic THP-1 cells. A mechanistic analysis revealed that the cAMP analog, dibutyryl cyclic AMP (dbcAMP), or the adenyl cyclase activator, forskolin, effectively suppressed the stimulant-induced TNF-alpha production by reducing the nuclear translocation and DNA binding activity of NF-kappaB. The inhibitory mechanisms manifested by dbcAMP included the decreased phosphorylation/degradation of NF-kappaB inhibitor (IkappaB) followed by its increased synthesis/stability. Importantly, this macrophage derived TNF-alpha appears to be a key pathological mediator of the resultant neurotoxicity, which was attenuated by increased cAMP levels during macrophage stimulation with CT105. These findings provide evidence, which supports an important role of CT105 as a potent macrophage stimulator eliciting NF-kappaB-mediated inflammatory signals for excess TNF-alpha production, which in turn ultimately leads to the neurotoxicity. In addition, the detailed inhibitory mechanism of cAMP action implies that an increased cAMP level could be benefit against AD progression.
authors.affiliation: Department of Microbiology, College of Medicine, Division of Molecular Biology and Neuroscience, Medical Research Center, Ewha Womans University, 911-1, Mok-6-dong, Yangcheonku, 158-710, Seoul, South Korea. younghae@ewha.ac.kr
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Chong
authors.forename: Soon Ah
authors.initials: SA
authors.lastname: Shin
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ji Hee Lee
authors.initials: JH
authors.lastname: Kang
authors.forename: Yoo-Hun
authors.initials: YH
authors.lastname: Suh
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000276:immunology* / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000242:Cyclic AMP