γ-Secretase, notch, Aβ and Alzheimer's disease:: Where do the presenilins fit in?

Investigations into the proteolytic processing of amyloid precursor protein (APP) have provided insights into both the pathogenesis of Alzheimer's disease and an unusual form of regulated proteolytic processing within the membrane-spanning domains of several proteins, including APP, Notch and ErbB4. Some of the enzymes responsible for alpha- and beta-secretase cleavage have been identified, and these seem to be conventional proteolytic events. However, the molecular events that are involved in gamma-secretase cleavage within the transmembrane domain of these proteins are much more complex. The presenilins and nicastrin are required for this process, but the role of the presenilins remains unclear. Although some data support the idea that the presenilins are in fact the active site of gamma-secretase, other data indicate that they might have a more indirect role-for example, in transporting substrates to the correct subcellular compartments for gamma-secretase cleavage.