They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop.

[4] Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein.

Presenilins play a key role in the modulation of intracellular Ca2+ involved in presynaptic neurotransmitter release and long-term potentiation induction.

[7][1] Presenilins undergo autocatalytic proteolytic processing after expression, cleaving a cytoplasmic loop region between the sixth and seventh helices to produce a large N-terminal and a smaller C-terminal fragment.

A 2006 study suggested a nine-pass transmembrane topology with cleavage and assembly into the gamma-secretase complex prior to insertion into the plasma membrane.

[8] Presenilins also have additional non-catalytic roles in other cellular signaling processes, including calcium homeostasis, lysosomal acidification, autophagy, and protein trafficking.

Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths.

[22] The genes for the presenilins were discovered in 1995 through linkage studies using mutations present in familial Alzheimer's disease cases.

[23] Although the function of the protein products of these genes was not immediately apparent, it became clear from subsequent work that the mutations were associated with higher proportions of Aβ42 over the less amyloidogenic Aβ40.

The role of presenilins as the catalytic component of the gamma secretase protein complex was established by the early 2000s.