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

Will your incompetent stroke doctors and stroke hospital do nothing to ensure this is tested in humans? Firings should commence immediately, starting with the board of directors.

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 and Valentin Fuster

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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.

Alzheimer’s disease (AD) is a progressive and multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, tau tangles, neuroinflammation, and brain atrophy (1). AD is strongly linked with cardiovascular risk factors, and is often accompanied by an important vascular component (2–4). The cerebrovascular pathology present in AD includes blood–brain barrier (BBB) disruption, neurovascular unit dysfunction, neurovascular uncoupling, and cerebral blood flow (CBF) alterations (5–7). Furthermore, chronic dysregulated hemostasis is present in AD, with increased thrombin generation, presence of activated platelets, and leakage of plasma proteins into the brain parenchyma (8,9), favoring the formation and persistence of fibrin clots (10,11).

Fibrin(ogen) is up-regulated early in AD (12), is found intravascularly and extravascularly in areas of synaptic dysfunction and amyloid pathology (10,11), and interacts with Aβ (13,14) inducing the formation of resistant clots (10,15). Because decreasing systemic fibrin(ogen) levels in AD mice ameliorates disease progression (10,11,16), therapeutics that normalize the prothrombotic environment present in AD might be useful in combination with other strategies (17). Indeed, traditional anticoagulants have been reported to be beneficial for dementia patients (18,19) and AD mouse models (20,21). However, to overcome their important limitations, such as the necessity for close monitoring and the high risk of bleeding, direct oral anticoagulants (DOACs) have emerged as a useful alternative (22). Among these, dabigatran is a potent oral direct thrombin inhibitor already approved for several indications, such as the prevention of stroke in patients with nonvalvular atrial fibrillation and the treatment of venous thromboembolism (23). Dabigatran has minimal drug–drug interactions (22), a low risk of intracranial bleeding (24,25), a potent anti-inflammatory effect (26), and an effective reversal agent available (27).

Here, we present evidence that long-term anticoagulation with dabigatran ameliorates multiple features of AD pathogenesis. Dabigatran treatment preserved memory and cerebral perfusion in transgenic AD mice, which was accompanied by improved BBB integrity, together with lower levels of fibrin, amyloid deposition, and neuroinflammatory activity in the AD brain.