Among other roles in the cell, secretases act on the amyloid precursor protein (APP) to cleave the protein into three fragments. Sequential cleavage by β-secretase (BACE) and γ-secretase produces the amyloid-β peptide fragment that aggregates into clumps called "plaques" in the brains of Alzheimer's disease patients. If α-secretase acts on APP first instead of BACE, no amyloid-β is formed because α-secretase recognizes a target protein sequence closer to the cell surface than BACE. The non-pathogenic middle fragment formed by an α/γ cleavage sequence is called P3.

The structure of the three sectretases varies widely. The α-secretase gene has not been conclusively identified but is believed to be a metalloproteinase. BACE is a transmembrane protein with an extracellular aspartic acid protease domain. γ-secretase is actually a protein complex containing presinilin, nicastrin, ACH-1, and PEN-2. Presinilin is believed to harbor the protease domain and represents an important example of a rare type of protease that cleaves targets within the cell membrane.

Besides their involvement in the pathogenesis of Alzheimer's, these proteins also have other functional roles in the cell. γ-secretase plays a critical role in developmental signalling by the transmembrane receptor Notch, freeing the cytoplasmic tail of Notch to travel to the cell nucleus to act as a transcription factor. Although BACE cleaves the extracellular domains of several transmembrane proteins, its physiological function remains unknown.

Enzymes | Integral membrane proteins | Biochemistry