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J Am Coll Cardiol. 2019 Oct 15;74(15):1910-1923. doi: 10.1016/j.jacc.2019.07.081.

Long-Term Dabigatran Treatment Delays Alzheimer's Disease Pathogenesis in the TgCRND8 Mouse Model.

Author information

1
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; The Rockefeller University, New York, New York. Electronic address: mcortes@cnic.es.
2
The Rockefeller University, New York, New York.
3
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
4
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Universidad Complutense de Madrid, Madrid, Spain.
5
Philips Healthcare Iberia, Madrid, Spain.
6
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Universidad Complutense de Madrid, Madrid, Spain; CIC biomaGUNE, Donostia-San Sebastián, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
7
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; IIS-Fundación Jiménez Díaz, Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
8
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York.

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.

KEYWORDS:

animal models of human disease; cognitive impairment; neuroinflammation; oral anticoagulation; thrombin; thrombosis

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