Macromolecular complex in recognition and proteolysis of amyloid precursor protein in Alzheimer's disease.

Proteolysis of amyloid precursor protein (APP), first extracellularly by β-secretase and then within the membrane by γ-secretase, produces β-amyloid peptides (Aβ). Aβ accumulates in the brain to form amyloid plaques, a hallmark of Alzheimer's disease (AD). Mutations in APP and presenilin (the catalytic subunit of γ-secretase) result in early onset of AD. Cryogenic electron microscopy (cryo-EM) structures of substrate-free and substrate-bound γ-secretase, determined at atomic resolutions, reveal the physical basis of distinct substrate specificity. These advances, together with the discovery and characterization of multiple proteins that interact with APP or presenilin, have given rise to an optimistic scenario for future mechanistic understanding of AD.