Anti-cis P-tau attenuates tauopathy and enhances cognitive function following global cerebral ischemia in mice

Global cerebral ischemia/reperfusion (GCI/R) induces widespread neuronal degeneration, accompanied by tauopathy in the hippocampus and profound cognitive impairment. Tau, a microtubule-associated protein highly expressed in neurons, becomes neurotoxic upon hyperphosphorylation, disrupting mitochondrial integrity and destabilizing microtubule architecture. Despite extensive efforts, no practical therapeutic approach has emerged to counter tau-related pathology. This study established a murine GCI/R model using three cycles of bilateral common carotid artery occlusion (5 min per cycle) with 5-min reperfusion intervals. The presence of cis P-tau and cognitive deficits in the hippocampus was confirmed following GCI/R. Treatment with a cis P-tau-targeted monoclonal antibody effectively prevented cognitive deterioration and attenuated ultrastructural brain damage. These findings demonstrate that GCI/R promotes pathogenic tau formation and contributes to cognitive dysfunction. Targeting cis P-tau may represent a viable therapeutic strategy to mitigate neurodegeneration and support cognitive recovery following global cerebral ischemic injury.