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

Marta Cortes-Canteli, Anna Kruyer, Irene Fernandez-Nueda, Ana Marcos-Diaz, Carlos Ceron, Allison T. Richards, Odella C. Jno-Charles, Ignacio Rodriguez, Sergio Callejas, Erin H. Norris, Javier Sanchez-Gonzalez, Jesus Ruiz-Cabello, Borja Ibanez, Sidney Strickland, Valentin Fuster

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageEnglish
Pages (from-to)1910-1923
Number of pages14
JournalJournal of the American College of Cardiology
Volume74
Issue number15
DOIs
StatePublished - 15 Oct 2019

Keywords

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

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