Factors Modulating tau Expression and Phosphorylation in Brain Cells

Abstract

Background: Neurodegenerative diseases (NDs) are defined as a set of disorders in the brain characterized by two interconnected pathological phases: neuronal cell damage and death, and neuroinflammation. A group of neurodegenerative diseases is the taupathies. This group possesses similar inflammatory characteristics accompanied by an alteration of tau protein structure and function. Tau protein is a microtubule-associated protein that works for the stability of microtubules in neurons. The function of tau is modulated by several post-translational modifications, mainly phosphorylation, and hyperphosphorylation of tau has been shown to be associated with microtubule destabilization, resulting in neuronal dysfunction, ultimately leading to neurodegenerative diseases. Thus, the factors that promote tau expression and phosphorylation are not yet fully defined. We have recently demonstrated that the plasma kallikrein-kinin system (KKS) is a modulator of neuroinflammation in microglial cells and in response to traumatic brain injury (TBI). However, the link between the KKS in modulating tau protein expression and phosphorylation has not been fully explored. Aims: In this study, we aim to investigate the impact of TBI and aging on the development of tau-related pathologies and determine the mechanisms by which KKS promote tau expression and phosphorylation. Methods: Mice were classified into four groups are: young SHAM, young TBI, old SHAM, and old TBI. TBI was performed on the right parietal cortex of C57BL/6J mice. The changes in KKS components and tau gene expression levels were assessed. To determine the effect of KKS on tau expression, phosphorylation, and nuclear translocation, murine N9 microglial cells and rat PC12 pheochromocytoma cells were used in these studies. The delineate of the receptor mechanism by which KKS affecting tau protein and gene was studied through inhibiting B2R and PAR2 receptors. Results: From previous data we found that KKS is activated through aging and post-TBI. Our results showed that TBI-aging combination significantly elevated tau gene expression level in brain cortex. In addition, we find that LPS (Lipopolysaccharide), bradykinin (BK), and plasma prekallikrein (Pkall) increased tau expression and phosphorylation in both N9 and PC12 cells. Moreover, we have also demonstrated that BK and PKall can induce the nuclear translocation of phosphorylated tau from the cytosol to the nucleus and this effect is mediated via bradykinin 2 receptors (B2R) and protease activated receptor 2 (PAR2). Conclusion: The findings of this study offer new insights into the role of the KKS in taupathies. They provide a potential target for the development of innovative therapeutic strategies aimed at mitigating tau-driven neuroinflammation.