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

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 (WT) littermates were treated for one year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling (ASL). At the molecular level, western blot (WB) 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 (AQP4) 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.

Anticoagulants for Treatment of Alzheimer’s Disease

“…However, it will be the task, first of preclinical research in AD mouse models, to study, if indeed this therapeutic approach is able to counteract effectively cerebrovascular dysfunction, present in AD pathogenesis. Interestingly, in the meantime, Cortes-Canteli and co-workers (2019) have reported results in AD mouse model, which are in line with the presented hypothesis [90]. Long-term treatment with dabigatran etexilate prevented memory decline, hypoperfusion, and fibrin deposition in the brain [90].…”

Altered Waste Disposal System in Aging and Alzheimer’s Disease: Focus on Astrocytic Aquaporin-4

“…Similarly, in a rat model of traumatic brain injury (TBI), acute administration of the hormone ghrelin was able to prevent post-TBI upregulation of AQP-4 expression (Lopez et al, 2012). Chronic treatment with dabigatran etexilate, a thrombin inhibitor, showed an indirect effect on AQP-4, preventing its misplacement found in TgCRND8 mice, a mouse model of AD (Cortes-Canteli et al, 2019). Thus, converging evidence demonstrates that targeting AQP-4 seems to be a promising pharmacological approach in several brain pathologies.…”

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

“…Conventional anti-coagulation treatments however carry the increased risk of bleeding, in particular in patients with CAA [28]. Novel type of anticoagulants have been developed that do not affect physiological hemostasis, and which raise the possibility for safe anticoagulation for AD patients [144,187]. Importantly, such treatments have also been shown to preserve pericyte morphology, BBB integrity and rCBF [187].…”