2024-03-28T08:40:01Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/85422023-10-05T05:48:28Zcom_20.500.12105_2152com_20.500.12105_2051com_20.500.12105_2144com_20.500.12105_2145col_20.500.12105_2153col_20.500.12105_2146
00925njm 22002777a 4500
dc
Cortes-Canteli, Marta
author
Kruyer, Anna
author
Fernandez-Nueda, Irene
author
Marcos-Diaz, Ana
author
Ceron, Carlos
author
Richards, Allison T
author
Jno-Charles, Odella C
author
Rodriguez, Ignacio
author
Callejas, Sergio
author
Norris, Erin H
author
Sanchez-Gonzalez, Javier
author
Ruiz-Cabello, Jesus
author
Ibáñez, Borja
author
Strickland, Sidney
author
Fuster, Valentin
author
2019-10
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.
J Am Coll Cardiol. 2019; 74(15):1910-1923
0735-1097
http://hdl.handle.net/20.500.12105/8542
31601371
10.1016/j.jacc.2019.07.081
1558-3597
Journal of the American College of Cardiology
Animal models of human disease
Cognitive impairment
Neuroinflammation
Oral anticoagulation
Thrombin
Thrombosis
Long-Term Dabigatran Treatment Delays Alzheimer's Disease Pathogenesis in the TgCRND8 Mouse Model