title: Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration.
abstract: Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNFR2, an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNFR2into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.
authors: Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, Faculty of Mathematics and Natural Sciences, University of Groningen, NL-9700 CC Groningen, The Netherlands.
authors: Yun
authors: Y
authors: Dong
authors: Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
authors: Roman
authors: R
authors: Fischer
authors: Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, Faculty of Mathematics and Natural Sciences, University of Groningen, NL-9700 CC Groningen, The Netherlands; Department of Neurology and Alzheimer Research Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Petrus J W
authors: PJ
authors: Naudé
authors: Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
authors: Olaf
authors: O
authors: Maier
authors: Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, Faculty of Mathematics and Natural Sciences, University of Groningen, NL-9700 CC Groningen, The Netherlands; Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, H-1088 Budapest, Hungary.
authors: Csaba
authors: C
authors: Nyakas
authors: Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
authors: Maëlle
authors: M
authors: Duffey
authors: Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, Faculty of Mathematics and Natural Sciences, University of Groningen, NL-9700 CC Groningen, The Netherlands.
authors: Eddy A
authors: EA
authors: Van der Zee
authors: Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, Faculty of Mathematics and Natural Sciences, University of Groningen, NL-9700 CC Groningen, The Netherlands; Department of Neurology and Alzheimer Research Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Doortje
authors: D
authors: Dekens
authors: Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, Faculty of Mathematics and Natural Sciences, University of Groningen, NL-9700 CC Groningen, The Netherlands.
authors: Wanda
authors: W
authors: Douwenga
authors: Baliopharm AG, CH-4051 Basel, Switzerland.
authors: Andreas
authors: A
authors: Herrmann
authors: Baliopharm AG, CH-4051 Basel, Switzerland.
authors: Eric
authors: E
authors: Guenzi
authors: Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
authors: Roland E
authors: RE
authors: Kontermann
authors: Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
authors: Klaus
authors: K
authors: Pfizenmaier
authors: Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, Faculty of Mathematics and Natural Sciences, University of Groningen, NL-9700 CC Groningen, The Netherlands; Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands u.l.m.eisel@rug.nl.
authors: Ulrich L M
authors: UL
authors: Eisel
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D020532:Basal Nucleus of Meynert / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D016923:Cell Death / Q000187:drug effects; D059329:Cholinergic Neurons / Q000187:drug effects / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016202:N-Methylaspartate / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000906:Antibodies; D002352:Carrier Proteins; C406446:EHD2 protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate
keywords: TNF; TNFR1; TNFR2; neurodegeneration; neuroprotection