PRESEN1LIN-INDEPENDENT AND JLK-SENSITIVE y-SECRETASE PATHWAY: A HOPE FOR ALZHEIMER'S DIESASE THERAPY?

摘要

Alzheimer's disease (AD) is characterized by the abnormal cortical deposition of a set of peptides referred to as amyloid p peptides (Ap). These peptides derive from the proteolytic processing of a large transmembrane precursor called pAPP by two enzymes, namely p- and y-secretases (Fig.1) that release the N- and C-terminus of Ap, respectively (for review see 1). Although the exact etiology of AD remains questionable, several lines of biochemical, anatomical and genetic evidence suggest that the Ap peptides at least contribute to the pathogenesis of AD. Along with this hypothesis, it can be postulated that blockade of secretases should hopefully lead to the reduction of Ap production and therefore, slow down or eventually prevent AD neurodegenerative process. In this context, a series of works aimed at identifying the nature of secretases have led to the unequivocal identification of the p-secretase as BACE (p-site APP Cleaving Enzyme). This new aspartyl protease appears mainly responsible for cerebral p-secretase activity as its genetic depletion abolishes the production of Ap in mice models of AD (for review see 2). The nature of putative y-secretase candidates is more discussed but it appears clearly that at least part of the y-secretase-mediated Ap production involves a multi-proteic complex in which the presenilins (PS) play a significant role (for review see 3). PS1 and PS2 are two related proteins which, when mutated give rise to aggressive forms of AD and it has been demonstrated that it is associated to an exacerbated production of Ap42, the more pathogenic species of the amyloid p peptides. On the other hand, the knock out of PS1 and PS2 abolishes the production of Ap in cells overexpressing the pAPP precursor (4). These data have led to the design of inhibitors of y-secretase that interact physically with PS and prevent Ap production. Altogether, these results have led to the proposal that presenilins would correspond to a new type of aspartyl protease bearing the y-secretase activity (5).