Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease.
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 AD (TgCRND8, PDAPP, and Tg2576), we evaluated blood-brain barrier damage and the role of fibrin and fibrinolysis in the progression of amyloid-beta 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. First, 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. Second, treatment of AD mice with the plasmin inhibitor tranexamic acid aggravated pathology, whereas removal of fibrinogen from the circulation of AD mice with ancrod treatment attenuated measures of neuroinflammation and vascular pathology. Third, pretreatment with ancrod reduced the increased pathology from plasmin inhibition. These results suggest that fibrin is a mediator of inflammation and may impede the reparative process for neurovascular damage in AD. Fibrin and the mechanisms involved in its accumulation and clearance may present novel therapeutic targets in slowing the progression of AD.
Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.
Justin
J
Paul
Sidney
S
Strickland
Jerry P
JP
Melchor
D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005337:Fibrin / Q000378:metabolism* / Q000502:physiology; D005340:Fibrinogen / Q000378:metabolism; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010539:Permeability; D010958:Plasminogen / Q000378:metabolism; D014148:Tranexamic Acid / Q000737:chemistry
D014148:Tranexamic Acid; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen