gamma-Secretase Modulators: ProductsMany membrane proteins also occur as in soluble forms due to proteolytic cleavage by secretases. alpha-, beta-, and gamma-secretases are best known for their cleavage of APP, the protein precursor of amyloid beta peptide (A beta), a major component of Alzheimer's disease plaques. Cleavage of APP by the beta- and gamma-secretases generates the Abeta peptide, while cleavage of APP by the alpha-secretase precludes the cleavage by the beta-secretase and prevents A beta production. The major candidates for the alpha-secretase are ADAM17/TACE, ADAM10, and ADAM9. BACE-1 is the major beta-secretase, although BACE-2 and Cathepsins D and E also have beta-secretase activity. The gamma-secretase is a multi-protein complex consisting of presenilin, nicastrin, APH-1, and PEN-2.