Targeting cis-p-tau and neuro-related gene expression in traumatic brain injury: therapeutic insights from TC-DAPK6 treatment in mice

Background: Traumatic brain injury (TBI) is a significant global health concern and is characterized by brain dysfunction resulting from external physical forces, leading to brain pathology and neuropsychiatric disorders such as anxiety. This study investigates the effects of TC-DAPK6 on tau hyper-phosphorylation, gene expression, anxiety, and behavior impairment in the TBI mice model. Methods and results: A weight drop model induced the TBI and the anxiety levels were evaluated using an elevated plus maze (EPM) test. TC-DAPK6 was intraperitoneally administered one-month post-TBI and continued for two months. The total cis-p-tau ratio in the brain was assessed using western blot and immunofluorescence staining. Molecular analysis was conducted on Aff2, Zkscan16, Kcna1, Pcdhac2, and Pcdhga8 to investigate the function and pathogenic role of TC-DAPK6 in neurological diseases in the cerebral cortex tissues of TBI-model mice, and the results were compared with TC-DAPK6 TBI-treatment group. The anxiety level and phosphorylation of tau protein in the TBI group were significantly increased compared to the sham groups and decreased substantially in the TBI-treatment group after TC-DAPK6 administration; the TBI group mostly spent their time with open arms. TC-DAPK6 decreased the expression level of genes as much as the sham group. Meanwhile, KCNA1 showed the highest fold of changes in the TBI and TBI-treatment groups. Conclusions: The study demonstrates a clear association between cis-p-tau and neuro-related gene expression levels in TBI-induced mice. Targeting these pathways with DAPK1 inhibitors, shows promise for therapeutic interventions in TBI and related neurodegenerative disorders.