Fibrin Deposition Accelerates Neurovascular Damage and Neuroinflammation in Mouse Models of AD

A characterisitc of Alzheimer's Disease in neurofibrillary tangles and amyloid plaques. It is these amyloid plaques that are beleived to be the reason for neurodegenitive degradation by acting either as a neurotoxin or an inflammatory response. Fibrinogen (a precursor to and the inactive form of Fibrin) is a stabilizing component of blood clots. Typically it is not seen in the central nervous system because of its inability to penetrate the blood brain barrier. However, with neurological damage, fibrinogen in able to enter the brain's vascular system. In patients and mouse models with AD, researchers have noticed an increased deposition of fibrinogen. In those with an increase in the protein, wound healing is impaired and there seems to be a higher mortality rate. Because inflammation is seen in those patients with fibrinogen, it is beleived that fibrinogen either initiates or augments the degree of inflammation.
Paul et al. set out to examine this hypothesis by determining the blood brain barrier's permeability to fibrinogen in three mouse models. In mice with AD, they found both damage to the blood brain barrier (BBB) and fibrin, the active form of fibrinogen.
Paul et. al are confident that fibrin plays a role in AD progression. This is evident because they used a mouse model with AD to induce fibrin deposition and reduce fibrinolysis and the pathology worsened.
Paul et. al used Evan's Blue Dye (which binds to albumin; a protein found in the blood) to track the permeability of the blood brain barrier. Each of the three mice had different strains of AD which display different characteristics as far as disease progression and age of onset. It was consistent with each model that the BBB was comprimised due to the movement of this dye across the BBB. They biopsied portions of the cortex to determine endothelial cell health as well as its ability to repair itself upon inflicted damage. Endothelial cells showed reduced response to signaling indicating an inability to become aware of damage. The BBB showed to be permeable to albumin so it was assume that macromolecules such as fibrinogen would have access as well. So overtime, fibrinogen/fibrin would accumulate thereby increasing disease progression.
So based on this evidence, wouldn't it make sense to encourage fibrinolysis in the models to determine whether or not this slowed or halted disease progression? Paul et. al used this information to devise another experiment to test whether or not this would work. In the case of fibrinogen inhibition, the models seemed to have reduced inflammation and protected from degradation by plasmin (a protease). Plasmin works to destroy blood clots before the dislodge and become an embolism.
The only thing I found conclusive of the article was that fibrinogen/fibrin is an upstream mediator of inflammation. Does anyone know plasmin's role in AD. In this article it mentions that plasmin has damaging effects to the BBB as well.