Stroke-induced subventricular zone proliferation is promoted by tumor necrosis factor-alpha-converting enzyme protease activity

J Cereb Blood Flow Metab. 2007 Apr;27(4):669-78. doi: 10.1038/sj.jcbfm.9600390. Epub 2006 Aug 23.

Abstract

Cerebral stroke induces proliferation of subventricular zone (SVZ) neural progenitor cells in adult rodent brain. Tumor necrosis factor-alpha-converting enzyme (TACE) proteolysis sheds the nonamyloidogenic soluble ectodomain of the amyloid precursor protein (APP) and is a convertase for tumor necrosis factor-alpha (TNFalpha). The resulting soluble peptides of APP and TNFalpha are mitogenic for neural progenitor cells of the SVZ. Therefore, we hypothesized a role for TACE proteolysis in stroke-induced neurogenesis. Using laser-capture microdissection, we found TACE transcription was increased in SVZ cells of ischemic brain. Immunohistochemistry revealed TACE protein was upregulated in SVZ neuroblasts. Intraventricular infusion of tumor necrosis factor-alpha protease inhibitor-2 (TAPI-2) decreased bromodeoxyuridine incorporation in SVZ cells of rats subjected to middle cerebral artery occlusion. Furthermore, primary culture SVZ neurospheres from ischemic brain overexpress TACE and its substrates APP and TNF-alpha. These cells proliferated more rapidly, possessed increased TACE protease-dependent alpha-secretase activity, and released more soluble APP and TNFalpha compared with nonischemic control. In addition, TAPI-2 reduced SVZ neuroblast migration out of SVZ explants in vitro. These findings indicate TACE proteolysis as a promoter of stroke-induced SVZ progenitor cell neurogenesis, and suggest this protease activity may represent an attractive therapeutic target for stroke recovery.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADAM Proteins / metabolism
  • ADAM Proteins / physiology*
  • ADAM17 Protein
  • Amyloid beta-Protein Precursor / biosynthesis
  • Animals
  • Blotting, Western
  • Bromodeoxyuridine / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Cerebral Ventricles / pathology*
  • Dissection
  • Enzyme-Linked Immunosorbent Assay
  • Immunohistochemistry
  • Infarction, Middle Cerebral Artery / pathology
  • Lasers
  • Male
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stroke / pathology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Tumor Necrosis Factor-alpha
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, rat
  • Bromodeoxyuridine