Shifting a complex debate on γ-secretase cleavage and Alzheimer's disease

Abstract

EMBO J 31 10, 2261–2274 (2012); published online April 13 2012

Chávez-Gutiérrez et al (2012) examine the effects of Alzheimer’s disease (AD) causing presenilin (PSEN) and amyloid β precursor protein (APP) mutations on intramembrane cleavage catalyzed by γ-secretase. These data provide definitive insights that should settle the long-standing debate regarding the role of loss of function effects of PSEN mutations in AD etiology. They also provide additional insights into the complexities of γ-secretase cleavage that may help to guide future therapeutic discovery efforts not only in AD but in other indications.

Figure 1

Schematic of the Ihara model of γ-secretase cleavage and effects of FAD-linked mutations or GSMs on Aβ production. Mutations in PSEN or APP alter both overall efficiency of the initial ε-cleavage as well as the ε-site (indicated by the asterisks). Two major ε-cleavages in APP produce two ‘product lines’ that influence subsequent cleavages, ‘processivity’. As the TMD is trimmed by the sequential cleavages, the substrate can either be further processed or released from the complex; this is indicated by the transition from black to red in the Aβ48/49 product lines. PSEN and APP mutants can alter the processivity resulting in release of increased Aβ42/43. GSMs are proposed to increase processivity resulting in less Aβ42 and more Aβ38.