Presenilins and the gamma-secretase: still a complex problem

The presenilins form part of a complex of membrane proteins that are involved in the proteolytic cleavage of cell-surface molecules. This article reviews the history of the discovery of the presenilins, their role in the pathogenesis of Alzheimer's disease and in the metabolism of the amyloid-beta precursor protein. Unanswered questions about their biochemical mechanism of action and their effects on Ca2+ homeostasis are examined.