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Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):12304-12309. Epub 2016 Oct 10.

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration.

Author information

1
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.
2
Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
3
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.
4
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.
5
Baliopharm AG, CH-4051 Basel, Switzerland.
6
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.

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-scTNFR2 into 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.

KEYWORDS:

TNF; TNFR1; TNFR2; neurodegeneration; neuroprotection

PMID:
27791020
PMCID:
PMC5087045
DOI:
10.1073/pnas.1605195113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

A.H., K.P., and R.E.K. are named inventors of patents covering the ATROSAB technology. A.H. is owner of Baliopharm, which is developing ATROSAB for clinical use. E.G. is an employee of Baliopharm. R.E.K. is a named inventor covering the EHD2 technology.

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