Molecular mechanisms underlying cyclic AMP inhibition of macrophage dependent TNF-α production and neurotoxicity in response to amyloidogenic C-terminal fragment of Alzheimer's amyloid precursor protein

Young Hae Chong, Soon Ah Shin, Hyun Joo Lee, Ji Hee Lee Kang, Yoo Hun Suh

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

In the present study, we characterized the intracellular pathway involved in the macrophage production of tumor necrosis factor-α (TNF-α) 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-γ (IFN-γ) elicited a robust and sustained increase of TNF-α production due to enhanced TNF-α mRNA transcription, mediated via increased nuclear factor-kappaB (NF-κB) 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-α production by reducing the nuclear translocation and DNA binding activity of NF-κB. The inhibitory mechanisms manifested by dbcAMP included the decreased phosphorylation/degradation of NF-κB inhibitor (IκB) followed by its increased synthesis/stability. Importantly, this macrophage derived TNF-α 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-κB-mediated inflammatory signals for excess TNF-α 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.

Original languageEnglish
Pages (from-to)160-174
Number of pages15
JournalJournal of Neuroimmunology
Volume133
Issue number1-2
DOIs
StatePublished - Dec 2002

Keywords

  • Alzheimer's disease
  • Amyloidogenic CTs
  • cAMP
  • Macrophage activator
  • Neurotoxicity
  • NF-κB

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