Targeting TNF receptors as potential therapeutic approach in neurodegenerative disease
Natalia Orti Casan1, Harald Wajant2, Yingying Wu1, Valentina Pegoretti1, Fabian Richter3,
Roland Kontermann3, Klaus Pfizenmaier3 and Ulrich Eisel1
1Department of Molecular Neurobiology, GELIFES, University of Groningen, Netherland; 2Department of Internal Medicine II, University of Würzburg, Germany; 3Institute of Cell Biology and Immunology, University of Stuttgart, Germany
Numerous studies have revealed the pleiotropic functions of tumor necrosis factor alpha (TNF-α), and have linked it with several neurodegenerative disorders. However, 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. Novel approaches 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 various mouse models of brain diseases. In an acute model of Alzheimer's disease co-administration 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 indicating an essential role of TNFR2 in neuroprotection. These 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 a novel approach in treating neurodegenerative diseases.