Presenilins and the gamma-secretase: still a complex problem

Abstract

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.

Figure 1

Amyloidogenic processing of the β-amyloid precursor protein (APP) by BACE1 and γ-secretase. Initially, BACE1 cleaves APP on the N-terminal end of the Aβ sequence to yield a large secreted N-terminal fragment (sAPPβ) and a smaller membrane-associated C-terminal stub (C99), which is then cleaved by the γ-secretase complex to yield Aβ and an APP intracellular domain (AICD). Secreted Aβ aggregates in the extracellular environment to form neurotoxic oligomers.

Figure 2

Hypothetical model showing how γ-secretase/PS may cleave C99 to yield Aβ. In this model, PS contains 2 catalytic aspartyl residues (D) that form part of the active site. The two residues are in an aqueous environment formed by a pocket on one side of the membrane. After cleavage of APP by BACE1, the product, C99, is destabilised and slips into the active site where it is cleaved to form Aβ and the APP intracellular domain (AICD).