β-Amyloid orchestrates factor xii and platelet activation leading to endothelial dysfunction and abnormal fibrinolysis in alzheimer disease

Alzheimer disease (AD) is the most common form of dementia in humans. However, to date, the cause of sporadic AD (SAD), which is the most frequent form, is still unknown. Although it has not been possible to determine the origin of this disease, the amyloid hypothesis is one of the most accepted to explain the etiology of AD. This hypothesis proposes that the pathogenesis of AD is derived from the toxic effect produced by the amyloid-β (Aβ) peptide in the brain parenchyma, but it does not make clear how Aβ is capable of producing such damage. Furthermore, it has been observed that SAD is accompanied by disruptions in the vascular system, such as damage to the blood-brain barrier. This facilitates the transfer of some systemic proteins, such as fibrinogen, to the brain parenchyma, where Aβ is abundant. Therefore, this Aβ interacts with fibrinogen, which favors the formation of clots resistant to fibrinolysis, inducing a risk of thrombosis and neuroinflammation. Notably, Aβ is not only of neuronal origin; platelets also contribute to high Aβ production in the circulation. The Aβ present in circulation favors the activation of coagulation factor XII, which leads to the generation of thrombin and bradykinin. In addition to Aβ-induced platelet activation, all these events favor the development of inflammatory processes that cause damage to the brain vasculature. This damage represents the beginning of the toxic effects of Aβ, which supports the amyloid hypothesis. This review addresses the relationship between alterations in the vascular and hemostatic systems caused by Aβ and how both alterations contribute to the progression of SAD.