Influence of coagulation proteases on cognitive function

Introduction: A role of coagulation proteases, their receptors (including protease activated receptors, PARs) and fibrinolysis in the central nervous system (CNS) in health and disease is established. One important regulator of coagulation protease activity and signaling is thrombomodulin (TM), a mostly endothelial expressed protein, which mediates activation of the anticoagulant and cytoprotective protease activated protein C (aPC). TM expression and function is impaired in vascular disease and vascular aging, the latter often being accompanied by cognitive impairment.

We aim to answer the question whether TM^Pro/Pro mice (a Glu404Pro point mutation reduces TM-thrombin-dependent aPC generation by>90%) show phenotypical alterations in the brain and if yes, whether this is related to hypercoagulability or loss of aPC generation.

Method: We will use mouse models with different genotypes and interventions to investigate coagulation-dependent impairment of cognition using tests for locomotor activity, fear-related exploratory behavior and learning patterns.

Results: We show that mice with a partial loss of TM-function (TM^Pro/Pro mice) have impaired cognition and altered gene-expression in various cell-types in the CNS (snRNAseq results). Surprisingly, we could show that the cognitive impairment in TM^Pro/Pro mice was restored when crossing the TM^Pro/Pro mouse with a mouse carrying a hyperactivatable protein C transgene (aPC^high)

Conclusion: We suggest that loss of TM-function, as observed in vascular disease, may impair CNS function. These results extend previous work by the Isermann group showing an impaired myelination and increased ROS generation in the CNS in TM^Pro/Pro mice. We further aim to answer whether interventions restoring specific TM-functions may rescue the phenotype and whether an acquired loss of TM-function causes structural CNS-defects and impairs cognition. Answering these questions will provide important insights into the TM-function for CNS-related disease processes and provide important mechanistic hints.