Stroke-induced subventricular zone proliferation is promoted by tumor necrosis factor-alpha-converting enzyme protease activity.
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.
Katakowski
Mark
M
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
Chen
Jieli
J
Zhang
Zheng Gang
ZG
Santra
Manoranjan
M
Wang
Ying
Y
Chopp
Michael
M
D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology*; D000072198:ADAM17 Protein; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000473:pathology*; D004210:Dissection; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007834:Lasers; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat; D001973:Bromodeoxyuridine