Abstract
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 (TNFΔARE/+) that develops rheumatoid arthritis and Crohn’s disease. 5XFAD/TNFΔARE/+ mice showed significantly decreased amyloid deposition. Interestingly, microglia but not astrocytes were activated in 5XFAD/ TNFΔARE/+ 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 TNF-α. 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.
Highlights
AD mice21,22. 5XFAD mice, carrying a 3’-UTR modified human Tumor necrosis factor-α (TNF-α) transgene[23] (5XFAD/Tg197) that results in increased peripheral expression of huTNF-α protein, develop an AD-like phenotype along with TNF-induced inflammatory arthritis, which can be suppressed by peripheral treatment with infliximab, a monoclonal anti-huTNF-α antibody widely used for RA treatment in patients24. 5XFAD/Tg197 mice exhibit robust brain inflammation, with extensive microglial and astrocytic activation and increased meningeal and perivascular macrophage activation that compromises neuronal integrity and synaptic health, despite reduced amyloid deposition
These results suggest that the modification of the endogenous mouse TNF-α gene (muTNF-α) gene in the 5XFAD/TNFΔARE/+ mice has a major effect on the TNF-α levels of the periphery compared to the brain where expression of TNF-α is significantly lower compared to the periphery and shows no difference between 5XFAD/TNFΔARE/+ and 5XFAD mice
To evaluate the effect of muTNF-α 3′UTR modification on the APP processing enzymes we examined and quantified protein levels of key enzymes involved in APP processing and Aβ production, as TACE, BACE1 and ADAM10, as well as enzymes that constitute the γ-secretase complex as presenilin 1 (PS1), Nicastrin and Aph1. 5ΧFAD/TNFΔARE/+ and 5XFAD total brain protein extracts were analyzed by Western blot analysis using specific antibodies to detect the above APP processing proteins
Summary
We have previously shown that peripheral human TNF-α and anti-TNF-α therapy, currently used in RA treatment, play a significant role in modulating neuroinflammation, amyloid deposition and neuronal degeneration in AD mice21,22. 5XFAD mice, carrying a 3’-UTR modified human TNF-α (hu TNF-α) transgene[23] (5XFAD/Tg197) that results in increased peripheral expression of huTNF-α protein, develop an AD-like phenotype along with TNF-induced inflammatory arthritis, which can be suppressed by peripheral treatment with infliximab, a monoclonal anti-huTNF-α antibody widely used for RA treatment in patients24. 5XFAD/Tg197 mice exhibit robust brain inflammation, with extensive microglial and astrocytic activation and increased meningeal and perivascular macrophage activation that compromises neuronal integrity and synaptic health, despite reduced amyloid deposition. We have previously shown that peripheral human TNF-α and anti-TNF-α therapy, currently used in RA treatment, play a significant role in modulating neuroinflammation, amyloid deposition and neuronal degeneration in AD mice. These alterations in the 5XFAD/Tg197 brains, correlated with increased levels of peripheral human TNF-α, suggesting that peripheral TNF-α alone is able to modulate brain inflammation through a TNF-α dependent periphery-to-brain communication pathway. Our results provide further evidence for an association between systemic peripheral inflammation and AD pathogenesis and suggest peripheral TNF-α as a central link
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