“Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.”
Sujan Devkota, et al. – University of Kansas.
In this study, Devkota and colleagues found that presenilin-1 (PSEN1) mutations causing familial Alzheimer’s (FAD) show impaired processing of amyloid precursor protein (APP) upstream of the final cleavage events that produce secreted Aβ peptides. This builds on previous work from this group finding that APP mutations associated with FAD have a similar effect. Cryo-electron microscopy, molecular modeling, and fluorescent imaging suggest that these PSEN1 mutants trap APP and/or its intermediates, stalling the γ-secretase complex. Experiments in C. elegans using synthetic APP mutants capable of stalling γ-secretase and abolishing Aβ42 production can cause synapse loss, suggesting that the stalled complex is the causative agent rather than Aβ42 or the Aβ42/Aβ40 ratio.
This study complements the finding of Zoltowska et al, featured here last month, that high concentrations of human Aβ42 can inhibit γ-secretase’s ability to cleave APP and its other targets. The findings here explain how the dominant mutations associated with early-onset AD can cause symptoms to appear decades earlier than in sporadic AD, despite producing far less Aβ42 – they do not require Aβ42 to build up to high concentrations over time in order to cause γ-secretase inhibition.
