The Search for γ-Secretase and Development of Inhibitors

A considerable body of evidence has accumulated in recent years implicating the ß-amyloid protein (Aß) in the etiology of Alzheimer's disease (AD). The highly hydrophobic Aß can nucleate and form neurotoxic fibrils that are the principal components of the cerebral plaques characteristic of AD. Aß is formed from the amyloid-ßprecursor protein (APP) through two protease activities. First, ß-secretase cleaves APP at the Aß N-terminus, resulting in a soluble, secreted APP derivative (ß-APPs) and a 12 kDa membrane-retained C-terminal fragment. The latter is further processed to Aß by γ secretases, which cleave within the single transmembrane region. Other APP molecules can be cleaved by α-secretase within the Aß region, thus precluding Aß formation. Both β- and γ- secretase have become prime targets for the development of therapeutic agent that reduce Aβ production. β-Secretase has recently been identified as a new membrane-anchored aspartyl protease in the cathepsin D family. Inhibitor profiling, site-directed mutagenesis, and affinity labeling together have suggested that the multi-pass presenilins are γ-secretases, novel intramembrane-cleaving aspartyl proteases activated through autoproteolysis. In this article, we review the current knowledge of γ-secretase biochemistry and cell biology and the development of inhibitors of this important therapeutic target.