Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions

Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic A beta peptides. The shift in A beta length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential gamma-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer A beta peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic A beta. In contrast, E-A beta n stabilizers increase gamma-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic A beta production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of gamma-secretase/substrate stabilizing compounds for the prevention of AD.