Author + information
- Received June 21, 2019
- Revision received July 18, 2019
- Accepted July 28, 2019
- Published online October 7, 2019.
- Marta Cortes-Canteli, PhDa,b,∗ (, )@mcortescanteli,
- Anna Kruyer, PhDb,
- Irene Fernandez-Nueda, RTa,
- Ana Marcos-Diaz, RTa,
- Carlos Ceron, MBa,
- Allison T. Richards, BAb,
- Odella C. Jno-Charles, MBb,
- Ignacio Rodriguez, PhDa,c,
- Sergio Callejas, PhDa,
- Erin H. Norris, PhDb,
- Javier Sanchez-Gonzalez, PhDd,
- Jesus Ruiz-Cabello, PhDa,c,e,f,g,
- Borja Ibanez, MD, PhDa,h,i,
- Sidney Strickland, PhDb,∗ and
- Valentin Fuster, MD, PhDa,j,∗
- aCentro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- bThe Rockefeller University, New York, New York
- cUniversidad Complutense de Madrid, Madrid, Spain
- dPhilips Healthcare Iberia, Madrid, Spain
- eCIC biomaGUNE, Donostia-San Sebastián, Spain
- fIKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- gCiber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- hIIS-Fundación Jiménez Díaz, Madrid, Spain
- iCIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- jIcahn School of Medicine at Mount Sinai, New York, New York
- ↵∗Address for correspondence:
Dr. Marta Cortes-Canteli, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
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.
- animal models of human disease
- cognitive impairment
- oral anticoagulation
↵∗ Drs. Strickland and Fuster are joint senior authors.
This work was funded by a Proof-of-Concept Award from the Robertson Therapeutic Development Fund (Dr. Cortes-Canteli), The Rockefeller University; NINDS/NIH grant NIS106668 (Drs. Norris and Strickland); European Union's Seventh Framework Programme (FP7-PEOPLE-2013-IIF), grant agreement n° PIIF-GA-2013-624811 (Drs. Cortes-Canteli and Fuster), CNIC, Madrid, Spain; Miguel Servet type I research contract (CP16/00174 and MS16/00174 [Dr. Cortes-Canteli]), Instituto de Salud Carlos III (ISCIII), CNIC; Iniciativa de Empleo Juvenil (PEJ16/MED/TL-1231 [A. Marcos-Diaz] and PEJ-2018-AI/BMD-11477 [C. Ceron]) from Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid; European Regional Development Funds (FEDER “Una manera de hacer Europa”) and European Social Funds (FSE “El FSE invierte en tu futuro”); and with the support of the Marie Curie Alumni Association (Dr. Cortes-Canteli). The CNIC is supported by the ISCIII, the Spanish Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). CIC biomaGUNE is a Maria de Maeztu Unit of Excellence (MDM-2017-0720). Dr. Sanchez-Gonzalez is an employee of Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Mike Sharma, MD, served as Guest Associate Editor for this paper.
- Received June 21, 2019.
- Revision received July 18, 2019.
- Accepted July 28, 2019.
- 2019 The Authors