Cyclooxygenase-derived prostanoids modulate a-secretase activity

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The amyloid precursor protein (APP) is processed by two exclusive proteolytic pathways that are initiated by the a- and the b-secretases. Down regulation of the a-secretase activity is associated with increased levels of b-secretase products in brain, including amyloid b, and decreased levels of sAPPa, the product of a-secretase. Such decrease of protease activity is associated with aging in humans and with oxidative stress. Using human platelets researchers have obtained evidence that sAPPa release is highly regulated by the interplay of several prostaglandin receptors.

Secretion of sAPPa has been analyzed in human platelets in response to various agonists. Activation of the thromboxane (TP) receptor with a specific agonist U46,619 gave the same response as arachidonic acid (AA), suggesting that the effect of the fatty acid was mediated by thromboxane A2. The maximal effect was obtained with 500 nM of TP receptor agonist or 7.5 µM of AA. They showed that the effect of AA was antagonized by SQ29,548, a specific antagonist of the TP receptor, in a dose-dependent manner, confirming that this effect of AA was mediated through the TP receptor. Obtained results indicating that carbaprostacyclin (CP), a stable analog of prostacyclin, antagonized in a dose-dependent manner the effect of U46,619. Scientists found that at low nanomolar concentrations, PGE2 potentiates the effect of a sub-efficacious concentration of AA on sAPPa release from human platelet and observed that when platelets were activated simultaneously with both U46,619 and AA, the secretion of sAPPa was inhibited by AA in a dose-dependent manner. They have shown previously that oxidation of AA by prostaglandin H2 synthase-1 in human platelet leads to formation of very reactive g-ketoaldehydes, levuglandins and that they form covalent adducts with lysine residues. Accordingly, they showed that levuglandin prevents cleavage of a fluorescent substrate of a-secretase by purified ADAM10.

These results indicate that prostanoid receptors can either stimulate or inhibit a-secretase activity and that modification of the APP by levuglandins could prevent its cleavage by a-secretase. This evidence provides support for a new paradigm for the participation of cyclooxygenases in the development of Alzheimer’s disease. ...http://www.alz.org/icad/

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