Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, involved in Alzheimer's disease pathogenesis. Anti-TNF-α therapeutic approaches currently used in autoimmune diseases have been proposed as a therapeutic strategy in AD. We have previously examined the role of TNF-α and anti-TNF-α drugs in AD, using 5XFAD mice, and we have found a significant role for peripheral TNF-α in brain inflammation. Here we investigated the role of mouse TNF-α on the AD-like phenotype of 5XFAD mice using a knock-in mouse with deletion of the 3'UTR of the endogenous TNF-α (tnf ΔARe/+) that develops rheumatoid arthritis and Crohn's disease. 5XFAD/TNF ΔARe/+ mice showed significantly decreased amyloid deposition. Interestingly, microglia but not astrocytes were activated in 5XFAD/ tnf ΔARe/+ brains. This microglial activation was associated with increased infiltrating peripheral leukocytes and perivascular macrophages and synaptic degeneration. APP levels and APP processing enzymes involved in Aβ production remained unchanged, suggesting that the reduced amyloid burden can be attributed to the increased microglial and perivascular macrophage activation caused by TNFα. Peripheral TNF-α levels were increased while brain TNF-α remained the same. These data provide further evidence for peripheral TNF-α as a mediator of inflammation between the periphery and the brain. Alzheimer's disease (AD) is the most common cause of dementia among the elderly characterized by severe memory loss and cognitive impairment 1. Although beta-amyloid (Αβ) is traditionally accepted as the main initiator of the disease, numerous failed clinical trials targeting Αβ 2 have changed research focus on other factors involved in the disease as brain inflammation, commonly called neuroinflammation 3,4. Moreover, clinical and experimental studies have provided significant evidence that peripheral inflammation may be associated with increased neuroinflammation and accelerated AD progression. A number of pro-inflammatory molecules including TNF-α, have been implicated in AD pathogenetic process 5. TNF-α has been shown to colocalize with amyloid plaques in AD human brains and animal models 6,7 and elevated TNF-α levels have been detected in the serum and cerebrospinal fluid (CSF) of AD patients 6,8,9. TNF-α is a pleiotropic pro-inflammatory cytokine that mediates its effect through two different receptors, TNF-α receptor I (p55) and TNF-α receptor II (p75) 10. TNF-α central role in the pathogenesis of chronic autoimmune diseases like rheumatoid arthritis (RA), psoriasis and Crohn's disease 11-14 has led to the development of anti-TNF-α therapeutics widely used in the treatment of autoimmune diseases 15,16. Case studies have reported that treatment of AD patients with the anti-TNF-α agents currently used in RA or Crohn's disease, was beneficial and improved cognitive impairment 17-19 while epidemiological studies showed that AD risk is reduced in RA patients receiving anti-TNF-α agents 20. We have previously shown that peripheral human TNF-α and anti-TNF-α therapy, c...