In the brain of a healthy mouse, blood vessels keep dyes contained in the circulation and out of the brain. In the brain of a mouse model of Alzheimer's disease, the barrier's permeability is increased and allows the smaller molecular dye (red) to leak, while keeping the larger molecular dye (green) contained. This “leakiness” allows fibrin to escape and accumulate in the brain.

Cerebrovascular dysfunction contributes to the pathology and progression of Alzheimer's disease (AD) but the mechanisms are not completely understood. Using transgenic mouse models of Alzheimer's disease (TgCRND8, PDAPP, and Tg2576), members of the Strickland Laboratory evaluated blood brain barrier damage and the role of fibrin and fibrinolysis in the progression of β-amyloid pathology. These mouse models showed age-dependent fibrin deposition coincident with areas of blood-brain barrier permeability as demonstrated by Evans blue extravasation. Three lines of evidence suggest that fibrin contributes to the pathology: 1, AD mice with only one functional plasminogen gene and therefore with reduced fibrinolysis have increased neurovascular damage relative to AD mice. Conversely, AD mice with only one functional fibrinogen gene have decreased blood-brain barrier damage; 2, Treatment of AD mice with the plasmin inhibitor tranexamic acid aggravated pathology, while removal of fibrinogen from the circulation of AD mice with ancrod treatment attenuated measures of neuroinflammation and vascular pathology; 3, Pretreatment with ancrod reduced the increased pathology from plasmin inhibition. These results suggest fibrin is a mediator of inflammation and may impede the reparative process for neurovascular damage in AD. Therefore, biomedical fellow Justin Paul and Sidney Strickland have shown that fibrin and the mechanisms involved in its accumulation and clearance may present novel therapeutic targets in slowing the progression of AD.

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