alphasecretase

Alpha-secretase, sometimes written alphasecretase, is a term used to describe a family of proteolytic enzymes that cleave many type I transmembrane proteins within their extracellular regions. The best known substrate is the amyloid precursor protein (APP). Cleavage by alpha-secretase occurs within the Aβ sequence, producing a soluble APP fragment (sAPPα) and a membrane-bound C-terminal fragment (CTFα) that can be further processed by gamma-secretase to yield the APP intracellular domain and the p3 peptide. This pathway is referred to as non-amyloidogenic because it precludes the formation of the amyloid-β peptide.

Most alpha-secretase activity in humans is attributed to members of the ADAM (a disintegrin and metalloprotease) family, particularly ADAM10, with ADAM17 (also known as TACE) contributing in some tissues and contexts. These enzymes are zinc-dependent metalloproteases and are synthesized as inactive pro-enzymes that are activated by proteolytic removal of the pro-domain. They localize to the cell surface and are regulated by signaling pathways, intracellular trafficking, and inhibitors such as TIMP-3.

Beyond APP, alpha-secretases cleave a variety of other substrates, including Notch receptors, which ties their activity to essential processes in development and cell signaling. The balance between alpha-secretase and beta-secretase activities on APP influences amyloid-beta production and has been a focus in Alzheimer’s disease research. Therapeutic strategies aim to upregulate alpha-secretase activity to promote non-amyloidogenic processing, while considering potential effects on other substrates and signaling pathways. Ongoing research continues to define substrate specificity, regulation, and physiological roles of alpha-secretases across tissues.