Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Significance TNF is known to play an important role in various neurodegenerative diseases. However, anti-TNF therapeutics failed in clinical trials of neurodegenerative diseases. This failure is most likely due to antithetic effects of the TNF receptors in the central nervous system, whereby TNFR1 promotes inflammatory degeneration and TNFR2 neuroprotection. Here we show that novel TNFR-selective therapeutics, i.e., a TNFR1 antagonist and a TNFR2 agonist, block neuroinflammation and promote neuronal survival in a mouse model of neurodegeneration related to Alzheimer disease as well as other neurodegenerative diseases. Most important, neuroprotection mediated by the TNFR1 antagonist is abrogated by simultaneous blockade of TNFR2 activation, revealing that neuroprotection requires TNFR2 signaling and uncover why anti-TNF drugs failed in treatment of neurodegenerative diseases. 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.

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