Mark4 ablation attenuates the pathological phenotype in tauopathy model mice

Abstract

Abstract Background Accumulation of abnormally phosphorylated tau proteins is linked to various neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. However, what modifications of tau proteins cause disease phenotypes have not been fully understood. Microtubule affinity-regulating kinase 4 (MARK4) has been genetically and pathologically associated with Alzheimer’s disease and reported to enhance tau phosphorylation and toxicity in Drosophila and mouse traumatic brain-injury models but not in mammalian tauopathy models. Methods To investigate the role of MARK4 in tau-mediated neuropathology, we crossed P301S tauopathy model (PS19) and Mark4 knockout mice. Following standard behavior, biochemical, and histology analyses were performed to evaluate changes in PS19 pathological phenotype with and without Mark4. Results In this study, we demonstrated that Mark4 deletion ameliorated the tau pathology in a mouse model of tauopathy. In particular, we found that PS19 with Mark4 knockout showed reduced mortality and memory loss compared with those bearing an intact Mark4gene. These phenotypes were accompanied by reduced neurodegeneration and astrogliosis in response to the reduction of pathological forms of tau, such as those phosphorylated at Ser356, AT8-positive tau, and thioflavin S-positive tau. Conclusion Our data indicate that Mark4critically contributes to tau-mediated neuropathology, suggesting that MARK4 inhibition may serve as a therapeutic avenue for tauopathies.