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Altered clot formation and anticoagulation in a familial Alzheimer's disease mouse model

University of British Columbia

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading form of dementia. Its complex etiology is traditionally attributed to an increase in the production and aggregation of amyloid-beta (Aβ). However, vascular risk factors and related disorders are also associated with the development of AD. The mechanism by which these deficiencies lead to neurodegeneration remains unclear. An altered hemostatic state has increasingly been implicated in AD pathogenesis, with the majority of research focusing on the interaction between Aβ and fibrin. It was therefore of interest to assess previously uncharacterized components of coagulation and anticoagulation in a familial AD (FAD) mouse model. Clot formation was initially analyzed using platelet rich plasma, with aged AD mice exhibiting 40% shorter clotting times compared to age-matched controls. Thrombin generation revealed differences attributable to an altered clot integrity. AD mice may form clots composed of a dense network of thin fibrin strands, resistant to fibrinolysis. Correspondingly, antithrombin (AT) activity was also reduced. These changes were subject to age, occurring specifically in aged mice only. These data suggest a change in clot formation and integrity concomitant with the development of AD. The interaction between Aβ and AT was examined in vitro, with Aβ42 and Aβ40 decreasing AT activity in a concentration dependent manner. A clinical study evaluating prothrombotic markers revealed a trend towards lower AT activity in AD patients, though not statistically significant. The changes in clot formation and anticoagulation potentiating a prothrombotic state may be specific to the FAD mouse model, but may still contribute to the elucidation of AD pathogenesis.

Text

2013-10-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/45350

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/