{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:45:22Z","timestamp":1791996322332,"version":"4.4.0"},"reference-count":38,"publisher":"Society for Neuroscience","issue":"36","license":[{"start":{"date-parts":[[2011,3,8]],"date-time":"2011-03-08T00:00:00Z","timestamp":1299542400000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2010,9,8]]},"abstract":"<jats:p>Tumor necrosis factor \u03b1 (TNF-\u03b1) is a potent cytokine in neurodegenerative disorders, but its precise role in particular brain disorders is ambiguous. In motor neuron (MN) disease of the mouse, exemplified by the model wobbler (WR), TNF-\u03b1 causes upregulation of the metalloprotease-disintegrin ADAM8 (A8) in affected brain regions, spinal cord, and brainstem. The functional role of A8 during MN degeneration in the wobbler CNS was investigated by crossing WR with A8-deficient mice: a severely aggravated neuropathology was observed for A8-deficient WR compared with WR A8<jats:sup>+\/\u2212<\/jats:sup>mice, judged by drastically reduced survival [7 vs 81% survival at postnatal day 50 (P50)], accelerated force loss in the forelimbs, and terminal akinesis.<jats:italic>In vitro<\/jats:italic>protease assays using soluble A8 indicated specific cleavage of a TNF-\u03b1 receptor 1 (p55 TNF-R1) but not a TNF-R2 peptide. Cleavage of TNF-R1 was confirmed<jats:italic>in situ<\/jats:italic>, because levels of soluble TNF-R1 were increased in spinal cords of standard WR compared with wild-type mice but not in A8-deficient WR mice. In isolated primary neurons and microglia, TNF-\u03b1-induced TNF-R1 shedding was dependent on the A8 gene dosage. Furthermore, exogenous TNF-\u03b1 showed higher toxicity for cultured neurons from A8-deficient than for those from wild-type mice, demonstrating that TNF-R1 shedding by A8 is neuroprotective. Our results indicate an essential role for ADAM8 in modulating TNF-\u03b1 signaling in CNS diseases: a feedback loop integrating TNF-\u03b1, ADAM8, and TNF-R1 shedding as a plausible mechanism for TNF-\u03b1 mediated neuroprotection<jats:italic>in situ<\/jats:italic>and a rationale for therapeutic intervention.<\/jats:p>","DOI":"10.1523\/jneurosci.1520-10.2010","type":"journal-article","created":{"date-parts":[[2010,9,8]],"date-time":"2010-09-08T16:47:56Z","timestamp":1283964476000},"page":"12210-12218","source":"Crossref","is-referenced-by-count":72,"title":["Tumor Necrosis Factor-\u03b1 (TNF-\u03b1) Regulates Shedding of TNF-\u03b1 Receptor 1 by the Metalloprotease-Disintegrin ADAM8: Evidence for a Protease-Regulated Feedback Loop in Neuroprotection"],"prefix":"10.1523","volume":"30","author":[{"given":"J\u00f6rg W.","family":"Bartsch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Wildeboer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrit","family":"Koller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Naus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Rittger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia L.","family":"Moss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Minai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Jockusch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2010,9,8]]},"reference":[{"key":"2023041303461274000_30.36.12210.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2007.11.005"},{"key":"2023041303461274000_30.36.12210.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(01)00097-8"},{"key":"2023041303461274000_30.36.12210.3","doi-asserted-by":"publisher","DOI":"10.1038\/385729a0"},{"key":"2023041303461274000_30.36.12210.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1071924"},{"key":"2023041303461274000_30.36.12210.5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200213847"},{"key":"2023041303461274000_30.36.12210.6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.12.6814"},{"key":"2023041303461274000_30.36.12210.7","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ne.19.030196.002013"},{"key":"2023041303461274000_30.36.12210.8","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(00)00124-2"},{"key":"2023041303461274000_30.36.12210.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2006.12.004"},{"key":"2023041303461274000_30.36.12210.10","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0602-06.2006"},{"key":"2023041303461274000_30.36.12210.11","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-200209000-00002"},{"key":"2023041303461274000_30.36.12210.12","doi-asserted-by":"publisher","DOI":"10.1016\/0888-7543(92)90199-3"},{"key":"2023041303461274000_30.36.12210.13","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20221"},{"key":"2023041303461274000_30.36.12210.14","doi-asserted-by":"publisher","DOI":"10.2174\/138161209788682361"},{"key":"2023041303461274000_30.36.12210.15","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1159\/000111969","article-title":"Astrocyte overgrowth in the brain stem and spinal cord of mice affected by spinal atrophy, wobbler","volume":"10","author":"Laage","year":"1988","journal-title":"Dev Neurosci"},{"key":"2023041303461274000_30.36.12210.16","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.4049\/jimmunol.152.10.5070","article-title":"Lipopolysaccharide LPS-mediated soluble TNF receptor release and TNF receptor expression by monocytes. 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