Presenilin and γ -Secretase Activity: A Viable Therapeutic Target for Alzheimers Disease?

In this review, we discuss the γ-secretase protease complexes, which are responsible for the generation of amyloid-β peptides that constitutes the amyloid plaques of Alzheimers disease (AD). We begin with a brief review on the amyloid-β precursor protein (APP), its proteolytic cleavage and a brief discussion on the pathogenesis of AD. We then present the four major components of the γ-secretase complexes - presenilin, nicastrin, Aph-1, and Pen-2 and also introduce the importance of post-translational modification activity of the γ-secretase complexes. We then discuss the diversity of γ-secretase substrates and proposed biological functions. Next we review the current therapeutic strategies aimed at developing selective inhibitors of AD-associated γ-secretase activities. Finally, we present a discussion, which serves as a platform for further questions into the viability of γ-secretase as an AD therapeutic target. Keywords: Alzheimer's disease, Amyloid-beta (Aβ), gamma-secretase, presenilin, regulated intramembrane proteolysis, posttranslational modification