Control of hippocampal pKr-2 expression reduces neurotoxic symptoms in 5XFAD mice

Background and purpose There is a scarcity of information regarding the role of prothrombin kringle-2 (pKr-2), which can be generated by active thrombin, associated with hippocampal neurodegeneration and its mechanisms in Alzheimer's disease (AD). Experimental approach To assess the role of pKr-2 in association with the neurotoxic symptoms of AD, we determined pKr-2 protein levels in the postmortem hippocampal tissues of patients with AD and the hippocampi of five familial AD (5XFAD) mice compared to those of age-matched controls and wild-type (WT) mice, respectively. In addition, we investigated whether the hippocampal neurodegeneration and object memory impairments shown in 5XFAD mice were mediated by the control of pKr-2 upregulation. Key results Our results demonstrated that pKr-2 upregulation, which was not associated with amyloid beta aggregation in 5XFAD mice, was observed in the hippocampi of patients with AD and 5XFAD mice. The upregulation of pKr-2 expression was inhibited by both blood-brain barrier (BBB) reinforcement through caffeine supply and treatment with rivaroxaban, an inhibitor of factor Xa that is associated with thrombin production. Moreover, the control of pKr-2 expression diminished neurotoxic symptoms, such as hippocampal neurodegeneration and object recognition decline through neurotoxic inflammatory responses, in 5XFAD mice. Conclusion and implications We identified a novel pathological mechanism of AD mediated by abnormal accumulation of pKr-2, which functions as an important pathogenic factor in the adult brain via BBB breakdown. Thus, pKr-2 represents a novel target for AD therapeutic strategies and those of related conditions.