Blood-Derived Plasminogen Modulates the Neuroimmune Response in Both Alzheimer\u27s Disease and Systemic Infection Models

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects 44 million people worldwide. To date, there are no effective treatments that prevent progression or death from the disease. It is clear that AD development is multifactorial and can arise from genetic or lifestyle factors and that vascular dysfunction and inflammation play a role in the progression of the disease. Many cardiovascular factors associated with an increase in systemic infection have been linked to a risk of AD development and progression. However, the link between vascular risk factors, systemic inflammation, and the neuroinflammation characteristic of AD are not fully understood. Plasminogen is primarily a blood protein synthesized in the liver, which when cleaved into its active form, plasmin, plays roles in fibrinolysis, wound healing, cell signaling, and inflammatory regulation. Increasing evidence links plasminogen to the regulation of inflammatory responses in many organ systems of the body and implicates plasminogen in the progression of a diverse range of pathologies. I aimed to determine whether plasminogen plays a role in the regulation of neuroinflammation during AD progression. I showed that blood-derived plasmin is a regulator of brain inflammatory activation. Depletion of peripheral plasminogen in an AD mouse model through antisense oligonucleotide (ASO) technology lessened AD pathology and decreased glial cell activation in the brain, whereas an increase in plasmin activity through α2-antiplasmin ASO treatment exacerbated AD mouse pathology. Moreover, blood-derived plasminogen modulated the wild-type mouse brain’s neuroinflammatory response to peripheral lipopolysaccharide injection and this was mediated by the p11 receptor, suggesting a more global role for plasminogen in regulating inflammatory communication between the periphery and brain. These studies suggest a crucial role for peripheral plasmin in mediating neuroimmune cell activation and could provide a link to systemic inflammatory risk factors that are known to be associated with the development of AD and other neurological disorders