Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):12304-12309. doi: 10.1073/pnas.1605195113. Epub 2016 Oct 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Basal Nucleus of Meynert / metabolism
  • Basal Nucleus of Meynert / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Cell Death / drug effects
  • Cholinergic Neurons / drug effects
  • Cholinergic Neurons / pathology
  • HEK293 Cells
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / genetics
  • Inflammation / pathology
  • Mice
  • N-Methylaspartate / genetics
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / immunology
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type I / genetics*
  • Receptors, Tumor Necrosis Factor, Type II / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type II / genetics*
  • Receptors, Tumor Necrosis Factor, Type II / immunology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / genetics*


  • Antibodies
  • Carrier Proteins
  • EHD2 protein, human
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • N-Methylaspartate