Alzheimer’s disease (AD) is distinguished pathologically from other neurodegenerative disorders by cerebral plaques composed of amyloid β-peptides (Aβ). The amyloid hypothesis posits that Aβ, particularly the aggregation-prone 42-residue form (Aβ42), triggers a cascade of events culminating in neuronal loss. Aβ is produced from amyloid precursor protein (APP) via ectodomain shedding by β-secretase followed by intramembrane proteolysis of the remnant C-terminal fragment C99 by γ-secretase. Missense mutations in APP or presenilin, the catalytic component of γ-secretase, cause dominantly inherited early-onset familial AD (FAD). All FAD mutations are found in the substrate and enzyme that produce Aβ, providing strong support for the amyloid hypothesis. Nevertheless, doubts remain whether Aβ is the primary disease driver and most appropriate therapeutic target. γ-secretase first cleaves C99 to produce long Aβ peptides that are trimmed down in ∼3-residue intervals along two pathways: Aβ49→Aβ46→Aβ43→Aβ40 and Aβ48→Aβ45→Aβ42→Aβ38. In a previous study, we have discovered that FAD mutations in C99 and presenilin-1 (PSEN1) result in reduced processive proteolysis and stabilization of the enzyme-substrate (E-S) complex. Surprisingly, these stalled and stabilized FAD E-S complexes are synaptotoxic, even in the absence of Aβ production, suggesting a novel amyloid-independent mechanism for how FAD mutations trigger neurodegeneration. In this study, we have performed all-atom enhanced sampling simulations using a novel ligand Gaussian-accelerated molecular dynamics 3 (LiGaMD3) method on the WT E-S complexes bound to different Aβ peptides (Aβ42 and Aβ40). The LiGaMD3 simulations captured the dissociation of the Aβ42 and Aβ40 from the γ-secretase complex. We were also able to identify important low-energy conformations of the γ-secretase complex during peptide dissociation. Therefore, our LiGaMD3 simulations have revealed for the first time the dynamic mechanisms of Aβ amyloid dissociation from γ-secretase, a key step in pathogenesis of AD.
Keya Joshi (Sun,) studied this question.