Tumor Necrosis Factor Receptor 2 A Promising Target for Neurodegenerative Diseases

Elevated TNF levels have been associated with different autoimmune diseases, and deregulation of TNF expression and signaling can lead to chronic inflammation and tissue damage. Anti-TNF therapeutics has been used successfully to treat autoimmune diseases, such as rheumatoid arthritis, psoriasis, or inflammatory bowel disease.

Up-regulated TNF expression has also been associated with neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, stroke, and multiple sclerosis TNF can activate two different receptors on cells: Tumor Necrosis Factor Receptor 1 and Tumor Necrosis Factor Receptor 2.  They have opposing functions:triggering Tumor Necrosis Factor Receptor 1 signaling induces cell death, while triggering Tumor Necrosis Factor Receptor 2 signaling prevents it. Furthermore, there are two types of TNF: a soluble form, which activates only Tumor Necrosis Factor Receptor 1, and a membrane bound form, which activates both receptors.

The results which were published on in Proceedings of the National Academy of Sciences provide a rational base for previous failure of clinical studies with anti-TNF drugs in multiple sclerosis and Alzheimer’s disease and highlight the essential protective role of Tumor Necrosis Factor Receptor 2 in the central nervous system.

The authors show in an in vivo model of NMDA-induced cellular degeneration and loss of neuronal functions that both a TNFR2 selective agonist (EHD2–scTNFR2) and a TNFR1 antagonistic antibody (ATROSAB) protect from loss of cholinergic fibers and associated neurologic deficits. This study points the way into new way of treatment. Studying the therapeutic potential of Tumor Necrosis Factor Receptor 2 agonist such as EHD2–scTNFR2 and the Tumor Necrosis Factor Receptor 1 antagonist ATROSAB in treatment of neurodegenerative diseases is warranted.