Processive proteolysis by γ-secretase and the mechanism of Alzheimer's disease

gamma-Secretase is a membrane-embedded protease complex with presenilin as the catalytic component. Cleavage within the transmembrane domain of the amyloid beta-protein precursor (APP) by gamma-secretase produces the C-terminus of the amyloid beta-peptide (A beta), a proteolytic product prone to aggregation and strongly linked to Alzheimer's disease (AD). Presenilin mutations are associated with early-onset AD, but their pathogenic mechanisms are unclear. One hypothesis is that these mutations cause AD through a toxic gain of function, changing gamma-secretase activity to increase the proportion of 42-residue A beta over the more soluble 40-residue form. A competing hypothesis is that the mutations cause AD through a loss of function, by reducing gamma-secretase activity. However, gamma-secretase apparently has two types of activities, an endoproteolytic function that first cuts APP to generate a 48/49-residue form of A beta, and a carboxypeptidase activity that processively trims these longer A beta intermediates approximately every three residues to form shorter, secreted forms. Recent studies suggest a resolution of the gain-of-function vs. loss-of-function debate: presenilin mutations may increase the proportion of longer, more aggregation-prone A beta by specifically decreasing the trimming activity of gamma-secretase. That is, the reduction of this particular proteolytic function of presenilin, not its endoproteolytic activity, may lead to the neurotoxic gain of function.