Abstract
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.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference126 articles.
1. Die Häufigkeit von Demenzerkrankungen;Bickel;Inf. Dtsch. Alzheimer Ges. eV Selbsthilfe Demenz Berl.,2020
2. Stimulus package
3. Alzheimer’s disease drug development pipeline;Sabbagh;J. Prev. Alzheimers Dis.,2020
4. Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets
5. Die medikamentöse Behandlung der Demenz;Kurz;Inf. Dtsch. Alzheimer Ges. eV Selbsthilfe Demenz Berl.,2012
Cited by
13 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献