Long-Term Dabigatran Treatment Delays Alzheimer's Disease Pathogenesis in the TgCRND8 Mouse Model.
Alzheimer Disease
/ drug therapy
Amyloid
/ metabolism
Amyloid beta-Peptides
/ metabolism
Animals
Anticoagulants
/ administration & dosage
Blood-Brain Barrier
Cerebral Cortex
/ metabolism
Dabigatran
/ administration & dosage
Disease Models, Animal
Female
Fibrin
/ metabolism
Hemostasis
Hippocampus
/ metabolism
Maze Learning
Memory
Mice
Mice, Transgenic
Neurodegenerative Diseases
/ physiopathology
Perfusion
Thrombosis
animal models of human disease
cognitive impairment
neuroinflammation
oral anticoagulation
thrombin
thrombosis
Journal
Journal of the American College of Cardiology
ISSN: 1558-3597
Titre abrégé: J Am Coll Cardiol
Pays: United States
ID NLM: 8301365
Informations de publication
Date de publication:
15 10 2019
15 10 2019
Historique:
received:
21
06
2019
revised:
18
07
2019
accepted:
28
07
2019
entrez:
12
10
2019
pubmed:
12
10
2019
medline:
2
6
2020
Statut:
ppublish
Résumé
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. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31601371
pii: S0735-1097(19)37362-0
doi: 10.1016/j.jacc.2019.07.081
pmc: PMC6822166
mid: NIHMS1056340
pii:
doi:
Substances chimiques
Amyloid
0
Amyloid beta-Peptides
0
Anticoagulants
0
Fibrin
9001-31-4
Dabigatran
I0VM4M70GC
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1910-1923Subventions
Organisme : NINDS NIH HHS
ID : R01 NS106668
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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