Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα

Tumor necrosis factor receptor II(TNFRII) is one of the TNF receptor superfamily members and our recent pathological studies show that TNFRII is deficient in the brains of Alzheimer's disease (AD). However, the mechanisms of TNFRII in AD pathogenesis remain unclear. In the present study, by using the gene-targeting approach to delete TNFRII in AD transgenic mouse model, we found that, in the brain of APP23 mice with TNFRII deletion (APP23/TNFRII-/-), AD-like pathology, i.e. plaque formation and microglial activation, occurs as early as 6 months of age. To test whether the increased levels of Ab plaques was due to elevated Ab, we measured Ab and found that A beta levels indeed were significantly increased at this age. Because beta-secretase, BACE1, is critical enzyme for Ab production, we have examined BACE1 and found that BACE1 is increased in both protein levels and enzymatic activity as early as 6 months of age; Having shown that BACE1 promoter region contains NF-kappa B binding sites, we found that cytoplasmic NF-kappa B was elevated and SUMO1 binding to I kappa B alpha was decreased. To further verify these findings, we have overexpressed TNFRII and identified that overexpressing TNFRII can reverse the findings from APP23/TNFRII-/- mice. Altogether, our results demonstrate novel roles of TNFRII in the regulation of Ab production, suggesting a potential therapeutic strategy for AD by up-regulating TNFRII levels and elevating phosphorylated I kappa B alpha by SUMOylation.