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

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.