Interleukin-1α stimulates non-amyloidogenic pathway by α-secretase (ADAM-10 and ADAM-17) cleavage of APP in human astrocytic cells involving p38 MAP kinase

Sanghamitra Bandyopadhyay, Dean M. Hartley, Catherine M. Cahill, Debomay K. Lahiri, Naibedya Chattopadhyay, Jack T. Rogers

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Interleukin-1α (IL-1α) stimulates a disintegrin and metalloproteinase, ADAM-17 synthesis, consistent with activation of the soluble fragment of Amyloid Precursor Protein, APP, (sAPPα) in human primary astrocytes. To characterize the mechanism by which IL-1α promotes the non-amyloidogenic pathway of APP metabolism, we used U373 MG astrocytoma cells. IL-1α significantly increased levels of ADAM-10 and ADAM-17 mRNA in 16 hr. Upregulation of ADAM-17 mRNA by IL-1α was more pronounced despite higher basal levels of ADAM-10 mRNA. This pattern was also observed at the protein level with the upregulation of α-secretase. RNA interference (RNAi) of ADAM-10 and ADAM-17 inhibited IL-1α-stimulated sAPPα release and the effect was more pronounced with ADAM-17 RNAi. Concomitantly, the level of sAPPα was significantly increased by IL-1α in 48 hr; however, IL-1α stimulated cell-associated APP levels maximally at 6 h but the induction declined at 48 hr. IL-1α treatment of cells for 48 h reduced both intracellular and secreted levels of amyloid-β, Aβ-40, and Aβ-42 peptides. Multiple MAP kinases (MAPK), including MEK/ERK, p38 kinase, PI3 kinase (PI3K) but not JNK were involved in the regulation of IL-1α-stimulated α-secretase activity and sAPPα release. p38 MAPK seems to be the most proximal of these MAPKs, as it was the earliest to be activated by IL-1α and blocking this pathway attenuated activation of IL-1α-induced MEK and PI3K pathways. Our data show a complex mechanism of sAPPα regulation by IL-1α that involves ADAM-10, ADAM-17 and p38 MAPK upstream of MEK and PI3K.

Original languageEnglish (US)
Pages (from-to)106-118
Number of pages13
JournalJournal of Neuroscience Research
Volume84
Issue number1
DOIs
StatePublished - Jul 1 2006

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Keywords

  • Alzheimer's disease
  • Inflammation
  • MAP kinase
  • Matrix metalloproteinase
  • RNA interference

ASJC Scopus subject areas

  • Neuroscience(all)

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