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.