ß-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-ß (Aß) peptide in the brain parenchyma, but it does not make clear how Aß 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 Aß is abundant. Therefore, this Aß interacts with fibrinogen, which favors the formation of clots resistant to fibrinolysis, inducing a risk of thrombosis and neuroinflammation. Notably, Aß is not only of neuronal origin; platelets also contribute to high Aß production in the circulation. The Aß present in circulation favors the activation of coagulation factor XII, which leads to the generation of thrombin and bradykinin. In addition to Aß-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 Aß, which supports the amyloid hypothesis. This review addresses the relationship between alterations in the vascular and hemostatic systems caused by Aß and how both alterations contribute to the progression of SAD.

Src, Akt, NF-κB, BCL-2 and c-IAP1 may be involved in an anti-apoptotic effect in patients with BCR-ABL positive and BCR-ABL negative acute lymphoblastic leukemia.

BCR-ABL kinase has been observed to be potentially related to leukemic cell development. Adult patients with acute lymphoblastic leukemia (ALL) were evaluated to determine whether presence/absence of BCR-ABL induced differences in activation of Src, PI3K/Akt and NF-κB or in the expression of anti-apoptotic proteins such as BCL-2 and c-IAP1. BCR-ABL positive patients showed a significantly higher activation of Src and Akt compared with BCR-ABL negative patients and healthy donors. BCR-ABL negative patients also showed a significant activation of Src and low levels of Akt activation compared with healthy donors. Both patient groups had increased NF-κB activation and overexpression of BCL-2 and c-IAP1. This is the first study to evaluate concurrently in ALL patients presence/absence of BCR-ABL in relation to activation of Src, Akt and NF-κB and the expression of anti-apoptotic proteins. Results suggest that these proteins may be involved in an anti-apoptotic signaling pathway.