Generation of Amyloid-β Peptides by γ-Secretase

gamma-Secretase is a four-component membrane-embedded aspartyl protease involved in the final cleavage step of the amyloid precursor protein (APP) to generate the amyloid-beta (A beta) peptide. Different amino-acid lengths of A beta peptide can be produced by this enzyme, of which the oligomerization and aberrant accumulation of the product containing 42 amino acids (A beta 42) has been associated with the development and formation of amyloid-beta plaques in the brain of Alzheimer's disease (AD) patients. Herein, we review some of the most important topics associated with the structure and activity of gamma-secretase and the factors that alter the substrate cleavage pattern, critical to the formation of the different isoforms of the amyloid-beta peptides.