Table two: The γ-Secretase Complex The γ -secretase is a complex of 4 proteins: 1) Presenilin-1 (PSEN1) 2)Presenilin enhancer-2 (PSEN2) 3) Nicastrin 4) Anterior pharynx-defective 1 (APH-1) The production of Aβ isoforms (39-42) takes place during the amyloidogenic pathway in which the intregal membrane protein APP undergoes proteolysis in two steps: Step one: The β-site amyloid precursor protein enzyme- BACE-1 removes (proteolysis) the sAPPβ portion of APP while the resulting protein remains positioned in the neuron cell membrane. Step two: Regulated intramembranous proteolysis is performed by γ-secretase.  This step releases Aβ isoforms (39-42) from the neuronal cell membrane. There are two presenilin proteins in the γ-secretase complex.  This is why mutations in these two presenilin genes are strongly correlated with AD.  It is proposed that the mutations can cause the production of abnormal versions of these two proteins which leads to improper proteolytic cleavage by the γ-secretase complex.

Table 2: The γ-Secretase Complex.