Long-term Dabigatran treatment delays Alzheimer’s disease pathogenesis in the TgCRND8 mouse model
Entity
UAM. Departamento de MedicinaPublisher
Elsevier on behalf of the American College of Cardiology FoundationDate
2019-10-15Citation
10.1016/j.jacc.2019.07.081
Journal of the American College of Cardiology 74.15 (2019): 1910-1923
ISSN
0735-1097DOI
10.1016/j.jacc.2019.07.081Editor's Version
https://doi.org/10.1016/j.jacc.2019.07.081Subjects
Animal models of human disease; Cognitive impairment; Neuroinflammation; Oral anticoagulation; Thrombin; Thrombosis; MedicinaRights
© 2019 The AuthorsEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
BACKGROUND Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with important vascular and
hemostatic alterations that should be taken into account during diagnosis and treatment.
OBJECTIVES This study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin
inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD.
METHODS TgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or
placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling.
At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid
burden, neuroinflammatory activity, and blood–brain barrier (BBB) integrity.
RESULTS Anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition
in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid
plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively.
Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of
the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB.
CONCLUSIONS Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive
thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and
amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.
Files in this item
Google Scholar:Cortes-Canteli, Marta
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Kruyer, Anna
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Fernández-Nueda, Irene
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Marcos-Díaz, Ana
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Ceron, Carlos
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Richards, Allison T.
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Jno-Charles, Odella C.
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Rodríguez, Ignacio
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Callejas, Sergio
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Norris, Erin H.
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Sánchez-Gonzáez, Javier
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Ruiz-Cabello, Jesús
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Ibáñez, Borja
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Strickland, Sidney
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Fuster, Valentín
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