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.

Platelet activation as a trigger factor for inflammation and atherosclerosis.

Platelets, in addition to participating in atherosclerosis, play a very active role in the immune response of this disease since they have the ability to interact with various inflammatory cells, in addition to secreting cytokines, chemokines, growth factors, etc. The functions of platelets go beyond their interaction with the endothelium, as they participate in creating an inflammatory environment, which contributes to the loss of homeostasis. On the other hand, platelet-derived microparticles induce the activation of other platelets, of endothelial cells and in recruiting leukocytes. For all the above, platelets and the inflammatory environment can be considered as possible therapeutic targets to prevent the development of atherosclerosis and the events associated with it.

Las plaquetas, además de participar en la ateroesclerosis, desempeñan un papel muy activo en la respuesta inmunitaria de esta enfermedad, ya que tienen la capacidad de interaccionar con diversas células inflamatorias, además de secretar citocinas, quimiocinas, factores de crecimiento, etc. Las funciones de las plaquetas van más allá de su interacción con el endotelio, pues participan en crear un ambiente inflamatorio, lo que contribuye a la pérdida de la homeostasis. Por otra parte, las micropartículas derivadas de plaquetas inducen la activación de otras plaquetas y de células endoteliales, y el reclutamiento de leucocitos. Por todo lo anterior, las plaquetas y el ambiente inflamatorio pueden considerarse como posibles blancos terapéuticos para evitar el desarrollo de la ateroesclerosis y los eventos asociados a esta.

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.

Molecular and functional characterization of an Entamoeba histolytica protein (EhMLCI) with features of a myosin essential light chain.

Entamoeba histolytica, a protozoan parasite of humans, relays on its striking motility to survive and invade host tissues. Characterization of the molecular components involved in motile processes is crucial to understand its pathogenicity. Although protein components of myosin II hexamers have been predicted from E. histolytica genome data, only a heavy chain of myosin, EhmhcA, has been characterized so far. We have cloned an E. histolytica cDNA sequence that best matched Dictyostelium discoideum myosin essential light chain and found that the cloned sequence is transcribed as an mRNA of 0.445 kb which could encode a protein of 16.88 kDa, within the predicted range for a myosin light chain. In silico analyses revealed that the protein sequence, named EhMLCI, shows two consensus domains for binding MHC, but lacks the N-terminal sequence for actin binding, as in A2 type myosin essential light chains. A single EF-hand calcium-binding domain was identified in the C-terminus and several high score predictability sites for serine and tyrosine phosphorylation. Antibodies to recombinant EhMLCI identified two proteins of approximately 17 and 15 kDa in trophozoite extracts, the latter phophorylated in tyrosines. Serine phosphorylation was not detected. Immunomicroscopy revealed EhMLCI cortical and cytoplasmic distribution in trophozoites and true colocalization with EhmhcA determined by PCC. Co-immunoprecipitation corroborated EhMLCI interaction with EhmhcA. EhMLCI was also localized in actomyosin-containing complexes. Differential partition of phospho-tyrosinated EhMLCI into cell fractions containing the soluble form of EhmhcA and its lack of serine phosphorylation suggest its possible participation in a novel down regulatory mechanism of myosin II activity in E. histolytica.

Mechanisms of cell volume regulation in hypo-osmolality.

Cells respond to a condition of hypo-osmolality by rapid swelling followed by an adaptive response that tends to recover the normal cell volume despite the persistence of the hypo-osmotic condition. This is an active process accomplished by the extrusion of intracellular osmolytes, essentially K+, Cl-, and small organic molecules. This regulatory process operates through a chain of events that essentially consists of a sensor or sensing mechanism to detect changes in cell volume, a signaling cascade to amplify the sensing signal and orient it to activate pathways for osmolyte extrusion, and a memory of the original cell volume, which sets the timing for inactivation of the volume-regulatory process. This article presents a brief overview of recent progress in these different aspects of the volume-regulatory process, including (1) the mechanisms and/or candidate molecules serving the role of volume sensors, (2) the osmosignaling network and the interplay and hierarchy of the different elements in this chain, and (3) the nature and properties of the osmolyte extrusion pathways. Emphasis is placed on some of the main unsolved questions concerning different aspects of the volume-regulatory process. Recent findings regarding the effect of hypo-osmolality on synaptic function are briefly discussed in terms of the possible molecular basis for the neurologic symptoms induced by hyponatremia.

Myosin I interactions with actin filaments and trans-golgi-derived vesicles in MDCK cell monolayers

In MDCK cell cultured monolayers, as well as in natural and other cultured epithelia, the proper organization of the actin filament ring, tethered to the plasma memebrane at the zonula adhaerens, is apparently necessary for their functioning as a transporting epithelium. It has been proposed that actin filaments, in conjunction with motor proteins, could provide the structural basis that regulates the tight junction (TJ) sealing capacity as well as the transport of memebrane-tagged proteins required for cell polarization. To test this hypothesis, the authors analyzed the localization and possible association ot the actin binding motor protein myosin I with actin filaments during changes in the actin ring position and organization, and also with tran-Golgi-derived vesicle. Modifications of the ring were induced subjecting the cells to external Ca²+ switch), or by treatment with drugs known to depolymerize actin filament (cytochalasin D, CD). The distribution of myosin I and actin, both in intact cells and in cellular fractions, was monitored using heterlogous cross-reacting antibodies and phalloidin. The authors identified an isoform of myosin I of approximately 110-125 KDa, homologus to myosin IB of Acanthamoeba, a fraction of wich colocalized with the peripheral actin ring. The association seems transient as, once the ring retracted as result of Ca²+ depletion, or became disroganized by CD, myosin not longer colocalized with the actin fibers but appeared dispersed in the cytoplasm. Furthermore, a signficant fraction of the total myosin I in the cell was associated to Golgi-derived vesicles which could also associate in vitro with actin filaments. The authors' data support, then, the participation of myosin I, in association with actin filaments, in vesicle translocation to and from the cell membrane as proposed for natural epithelia, and provide a further insigh into the structural organization that maintains epithelial cell polatiry in cultured monolayers