Direct Oral Anticoagulants (DOACs) for Therapeutic Targeting of Thrombin, a Key Mediator of Cerebrovascular and Neuronal Dysfunction in Alzheimer's Disease

Abstract

Although preclinical research and observer studies on patients with atrial fibrillation concluded that direct oral anticoagulants (DOACs) can protect against dementia like Alzheimer's disease (AD), clinical investigation towards therapeutical approval is still pending. DOACs target pathological thrombin, which is, like toxic tau and amyloid-ß proteins (Aß), an early hallmark of AD. Especially in hippocampal and neocortical areas, the release of parenchymal Aß into the blood induces thrombin and proinflammatory bradykinin synthesis by activating factor XII of the contact system. Thrombin promotes platelet aggregation and catalyzes conversion of fibrinogen to fibrin, leading to degradation-resistant, Aß-containing fibrin clots. Together with oligomeric Aß, these clots trigger vessel constriction and cerebral amyloid angiopathy (CAA) with vessel occlusion and hemorrhages, leading to vascular and blood-brain barrier (BBB) dysfunction. As consequences, brain blood flow, perfusion, and supply with oxygen (hypoxia) and nutrients decrease. In parenchymal tissue, hypoxia stimulates Aß synthesis, leading to Aß accumulation, which is further enhanced by BBB-impaired perivascular Aß clearance. Aß trigger neuronal damage and promote tau pathologies. BBB dysfunction enables thrombin and fibrin(ogen) to migrate into parenchymal tissue and to activate glial cells. Inflammation and continued Aß production are the results. Synapses and neurons die, and cognitive abilities are lost. DOACs block thrombin by inhibiting its activity (dabigatran) or production (FXa-inhibitors, e.g., apixaban, rivaroxaban). Therefore, DOAC use could preserve vascular integrity and brain perfusion and, thereby, could counteract vascular-driven neuronal and cognitive decline in AD. A conception for clinical investigation is presented, focused on DOAC treatment of patients with diagnosed AD in early-stage and low risk of major bleeding.

Keywords: Alzheimer´s disease; amyloid-beta; blood–brain barrier dysfunction; cerebral amyloid angiopathy; direct oral anticoagulants; fibrin; inflammation; tau; thrombin; vascular dysfunction.

Figure 1

Mechanism of action of direct oral anticoagulants (DOACs) in therapeutic treatment of vascular abnormalities, triggered by thrombin, a key factor in Alzheimer´s disease (AD). In addition to the accumulation of toxic tau and amyloid-ß proteins (Aß) in brain parenchyma, excessive production of thrombin in the blood, leading to fibrin formation; degradation-resistant, Aß-containing fibrin(ogen) clots; and inflammatory milieu are an early and typical hallmark of AD. Particularly in hippocampal and neocortical parenchyma, the release of Aß into the blood triggers the synthesis of thrombin and proinflammatory bradykinin. Aß activate blood coagulation factor XII to generate FXIIa in the plasma contact system. Thrombin, which is produced from prothrombin by the prothrombinase complex via factor Xa (FXa), catalyzes the conversion of fibrinogen to fibrin and induces, together with fibrin(ogen), platelet aggregation, which can lead to vessel occlusion. Deposition of oligomeric Aß and Aß-containing fibrin clots cause vessel constriction and cerebral amyloid angiopathy (CAA). CAA is a major cause in Aß-induced brain vasculopathies and associated lesions, such as vessel occlusion and hemorrhages, leading eventually to vascular and blood–brain-barrier (BBB) dysfunction. As consequences, cerebral blood flow (CBF) and perfusion decrease and supply of brain tissue with oxygen (hypoxia) and nutrients suffer. Concomitantly, Aß increasingly accumulate and aggregates spread in the parenchymal tissue, caused by hypoxia-induced Aß synthesis, as well as by BBB-impaired perivascular Aß clearance. This self-amplifying accumulation of Aß elicits neuronal hyperactivation and synaptic dysfunction and promotes neurotoxic tau pathologies. In addition, BBB dysfunction allows vascular thrombin and fibrin(ogen) to extravasate into the parenchymal tissue and to activate, together with Aß, glial cells, inducing chronic inflammation and further Aß production. In addition, neuronal damage with loss of synapses and neurons is progressing, leading to cognitive decline. DOAC intervention into this vicious circle targets the key mediator thrombin, which can be blocked in its activity by dabigatran or in its production by FXa-inhibitors, such as apixaban, rivaroxaban. Early thrombin inhibition in AD patients could preserve vascular and BBB integrity for full brain perfusion and function. Thereby, vascular-driven neuroinflammation and degeneration and associated cognitive decline could be prevented. Modified from [11].