Effects of the β-Amyloid and Carboxyl-terminal Fragment of Alzheimer's Amyloid Precursor Protein on the Production of the Tumor Necrosis Factor-α and Matrix Metalloproteinase-9 by Human Monocytic THP-1

Abstract

To explore the direct role of β-amyloid (Aβ) and carboxyl-terminal fragments of amyloid precursor protein in the inflammatory processes possibly linked to neurodegeneration associated with Alzheimer's disease, the effects of the 105-amino acid carboxyl-terminal fragment (CT 105) of amyloid precursor protein on the production of tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9) were examined in a human monocytic THP-1 cell line and compared with that of Aβ. CT 105 elicited a marked increase in TNF-α and MMP-9 production in the presence of interferon-γ in a dose- and time-dependent manner. Similar patterns were obtained with Aβ despite its low magnitude of induction. Autocrine TNF-α is likely to be a main mediator of the induction of MMP-9 because the neutralizing antibody to TNF-α inhibits MMP-9 production. Genistein, a specific inhibitor of tyrosine kinase, dramatically diminished both TNF-α secretion and subsequent MMP-9 release in response to CT 105 or Aβ. Furthermore, PD98059 and SB202190, specific inhibitors of ERK or p38 MAPK respectively, efficiently suppressed CT 105-induced effects whereas only PD98059 was effective at reducing Aβ-induced effects. Our results suggest that CT 105 in combination with interferon-γ might serve as a more potent activator than Aβ in triggering inflammatory processes and that both tyrosine kinase and MAPK signaling pathways may represent potential therapeutic targets for the control of Alzheimer's disease progression.