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J. Biol. Chem., Vol. 276, Issue 26, 23511-23517, June 29, 2001

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

Young Hae Chong^§¶, Ji Hye Sung, Soon Ah Shin, Jang-Hyun Chung, and Yoo-Hun Suh^**

From the Departments of  Microbiology and  Ophthalmology, College of Medicine, Division of Molecular Biology and ^§ Neuroscience, Medical Research Center, Ewha Womans University, 911-1, Mok-6-dong, Yangcheonku, Seoul, 158-056, Korea and the ^** Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul 110-799, South Korea

To explore the direct role of -amyloid (A) 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 (CT₁₀₅) of amyloid precursor protein on the production of tumor necrosis factor- (TNF-) and matrix metalloproteinase-9 (MMP-9) were examined in a human monocytic THP-1 cell line and compared with that of A. CT₁₀₅ elicited a marked increase in TNF- and MMP-9 production in the presence of interferon- in a dose- and time-dependent manner. Similar patterns were obtained with A despite its low magnitude of induction. Autocrine TNF- is likely to be a main mediator of the induction of MMP-9 because the neutralizing antibody to TNF- inhibits MMP-9 production. Genistein, a specific inhibitor of tyrosine kinase, dramatically diminished both TNF- secretion and subsequent MMP-9 release in response to CT₁₀₅ or A. Furthermore, PD98059 and SB202190, specific inhibitors of ERK or p38 MAPK respectively, efficiently suppressed CT₁₀₅-induced effects whereas only PD98059 was effective at reducing A-induced effects. Our results suggest that CT₁₀₅ in combination with interferon- might serve as a more potent activator than A 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.

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