RESUMO
For years, the prevailing hypothesis for Alzheimer's Disease (AD) has proposed a mechanism by which deposition of amyloid-beta (Aß) in the brain is independent of tau-pathologies and cognitive decline. However, despite extensive research on the disease, the mechanisms underlying the etiology of tau-pathology remain unknown. Previous research in our lab has shown that imatinib methanesulfonate (IM) blocks the peripheral production of Aß in response to LPS, thereby preventing the buildup of Aß in the hippocampus, and rescuing the cognitive dysfunction that normally follows. The present study aimed to examine the link between Aß and tau following inflammation, and to expand our understanding of how IM affects AD pathology. Specifically, we hypothesized that the IM-mediated inhibition of Aß production following inflammation would successfully protect against the hyperphosphorylation of tau (ptau). Here we show that 7days of LPS treatment in male C57BL/6J mice, which normally produces elevations in peripheral and central Aß, also produces hyperphosphorylation of tau. However, just as pre-treatment and concurrent treatment with IM blocks Aß production, it also blocks the phosphorylation of tau. In addition, 7days of LPS-induced inflammation and Aß production also leads to elevated total tau protein expression. Our results may provide support for the hypothesis that enhanced expression of tau following LPS administration is a protective measure by hippocampal neurons to compensate for the loss of the microtubule-stabilizing protein due to phosphorylation. More importantly, our results support the hypothesis that blocking the production of Aß that follows inflammation also leads to reduced tau phosphorylation, lending credence to a model in which Aß initiates tau phosphorylation.