Targeting fibrin in neurodegeneration

2021

IJMS

Alzheimer’s disease (AD) is caused by neurodegenerative, but also vascular and hemostatic changes in the brain. The oral thrombin inhibitor dabigatran, which has been used for over a decade in preventing thromboembolism and has a well-known pharmacokinetic, safety and antidote profile, can be an option to treat vascular dysfunction in early AD, a condition known as cerebral amyloid angiopathy (CAA). Recent results have revealed that amyloid-β proteins (Aβ), thrombin and fibrin play a crucial role in triggering vascular and parenchymal brain abnormalities in CAA. Dabigatran blocks soluble thrombin, thrombin-mediated formation of fibrin and Aβ-containing fibrin clots. These clots are deposited in brain parenchyma and blood vessels in areas of CAA. Fibrin-Aβ deposition causes microvascular constriction, occlusion and hemorrhage, leading to vascular and blood–brain barrier dysfunction. As a result, blood flow, perfusion and oxygen and nutrient supply are chronically reduced, mainly in hippocampal and neocortical brain areas. Dabigatran has the potential to preserve perfusion and oxygen delivery to the brain, and to prevent parenchymal Aβ-, thrombin- and fibrin-triggered inflammatory and neurodegenerative processes, leading to synapse and neuron death, and cognitive decline. Beneficial effects of dabigatran on CAA and AD have recently been shown in preclinical studies and in retrospective observer studies on patients. Therefore, clinical studies are warranted, in order to possibly expand dabigatran approval for repositioning for AD treatment.

Section: Alzheimer’s Disease—the Role Of Thrombin Fibrin and Amyloid-β-containing Fibrin Clotsmentioning

confidence: 99%

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

2021

IJMS

“…2). Parenchymal fibrin was shown to activate microglia cells by binding the fibrin epitope γ377-395 with the microglial receptor CR3, leading to inflammatory processes [72,73]. Accordingly, blocking of the fibrin epitope by antibody reduced cerebral inflammatory and degenerative processes in AD mouse model [72].…”

Section: Alzheimer's Disease: Pathophysiological Hallmarks and Currenmentioning

confidence: 99%

Anticoagulants for Treatment of Alzheimer’s Disease

2020

JAD

Alzheimer’s disease (AD) is a multifactorial syndrome with a plethora of progressive, degenerative changes in the brain parenchyma, but also in the cerebrovascular and hemostatic system. A therapeutic approach for AD is reviewed, which is focused on the role of amyloid–β protein (Aβ) and fibrin in triggering intra-brain vascular dysfunction and connected, cognitive decline. It is proposed that direct oral anticoagulants (DOACs) counteract Aβ-induced pathological alterations in cerebral blood vessels early in AD, a condition, known as cerebral amyloid angiopathy (CAA). By inhibiting thrombin for fibrin formation, anticoagulants can prevent accumulations of proinflammatory thrombin and fibrin, and deposition of degradation-resistant, Aβ-containing fibrin clots. These fibrin–Aβ clots are found in brain parenchyma between neuron cells, and in and around cerebral blood vessels in areas of CAA, leading to decreased cerebral blood flow. Consequently, anticoagulant treatment could reduce hypoperfusion and restricted supply of brain tissue with oxygen and nutrients. Concomitantly, hypoperfusion-enhanced neurodegenerative processes, such as progressive Aβ accumulation via synthesis and reduced perivascular clearance, neuroinflammation, and synapse and neuron cell loss, could be mitigated. Given full cerebral perfusion and reduced Aβ- and fibrin-accumulating and inflammatory milieu, anticoagulants could be able to decrease vascular-driven progression in neurodegenerative and cognitive changes, present in AD, when treated early, therapeutically, or prophylactically.

“…Fibrin protofibrils form a stable construct of cross-linked fibrin strands with integrated erythrocytes and platelets, known as a blood clot or thrombus. In addition, fibrin(ogen) can trigger inflammatory processes in neurodegeneration [ 17 , 18 ].…”

Section: Hemostasis Thrombosis and Antithrombotic Medicationmentioning

confidence: 99%

“…Just like thrombin, fibrin(ogen) can directly activate inflammatory glial responses and ROS generation [ 17 , 18 , 109 ]. This occurs by binding of the fibrin domain γ377–395 to the microglial CD11b/CD18 integrin surface receptor.…”

Section: Interaction Of Aß With the Plasma Contact System And Its Dri...mentioning

confidence: 99%

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

2022

Biomedicines

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 triggers neuronal damage and promotes 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.