Targeting TNF: a therapeutic strategy for Alzheimer's disease

• TNFα biosynthesis, TNF receptors, and signaling.
• Neurotoxicity of TNFα in the brain.
• TNFα receptor signaling-related neuron death and neuroprotection.
• TNF receptors and Alzheimer disease, including signaling pathways in APP processing, Aβ, and genetic risk of AD.
• Current status of anti-TNFα therapy in clinics and possible drug candidates for AD.

Tumor necrosis factor (TNF), a ligand cytokine, is involved in systemic inflammation. Apart from the well-known pharmacological effects of TNF inhibitors on autoimmune disorders, interest in the effects of TNF in neurodegenerative disorders such as Alzheimer disease (AD) is increasing. TNF and its type 1 receptor (TNFRI) are not only involved in AD-related brain neuroinflammation, but also contribute to amyloidogenesis via β-secretase regulation, suggesting TNF as a promising candidate for future AD therapy. Although the potential adverse effects of TNF-based AD therapies have been of concerns, here we summarize recent discoveries relating to TNF and TNFRI-mediated signal transduction as potential therapeutic targets in AD pathology and clinical investigations.