Chapter 2: Targeting Alzheimer's γ-Secretase: Genetic and Chemical Modulation

γ-Secretase mediates the proteolytic cleavage of amyloid precursor protein (APP) to generate amyloid β protein (Aβ), the major component of neuritic plaques found in brains of Alzheimer's disease (AD) patients. Exploring the nature of γ-secretase started with the cloning of the presenilin 1 (PS1) gene, in which the mutations are linked to most cases of early onset familial AD. Identification of two aspartate residues within PS1 revealed the core active site of the γ-secretase, and additional components of the functional γ-secretase complex include Nicastrin, APH-1 and PEN-2. These four components play intrinsic roles in controlling the γ-secretase cleavage of multiple substrates. Among them, APP and Notch are two most studied substrates. Different classes of γ-secretase inhibitors have been explored to block the cleavage of APP and the generation of toxic Aβ, however, they also block the γ-secretase cleavage of Notch to generate Notch Intracellular domain (NICD), a critical signaling molecule. APP-selective γ-secretase modulators have been developed, and some have shown potent inhibition of Aβ generation while spared Notch signaling. Finally, in vitro and in vivo studies have demonstrated that the key components of the γ-secretase complex such as Nicastrin and APH-1 are capable of modulating γ-secretase substrate recognition and Aβ production. Thus, γ-secretase, and its subunits in particular, continue to be one of the prime targets for the development of amyloid based AD therapies.