Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 27, Issue 4, Pages 669-678Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.jcbfm.9600390
Keywords
amyloid precursor protein (APP); amyloid-beta; neurogenesis; neural progenitor cells; stem and progenitor cells; tumor necrosis factor-alpha convertase (TACE)/ADAM17
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Funding
- NHLBI NIH HHS [R01HL64766] Funding Source: Medline
- NINDS NIH HHS [R01NS43324, P01NS23393] Funding Source: Medline
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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 (TNF alpha). The resulting soluble peptides of APP and TNF alpha 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 TNF alpha 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.
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