Understanding familial Alzheimer's disease: The fit‐stay‐trim mechanism of γ‐secretase

Understanding Alzheimer's disease is a central challenge of the 21st century, as affects tens millions people and kills million each year, with current drugs having modest effect. This article reviews how computational science integrating new cryo-electron microscopy structures biochemical clinical data has led to causative model familial (fAD). The model's basis open compact conformational states membrane protease γ-secretase, controlled by transmembrane helix “fingers” that hold substrate either tightly or loosely. two are in thermal equilibrium lead different amounts long short Aβ peptides, explaining much-debated Aβ42/Aβ40 ratio. Pathogenic mutations shift toward state reducing stability hydrophobic packing enzyme-substrate complex, which increases toxic Aβ42 other longer peptide forms compared Aβ40. In contrast, selectively target longer, pathogenic peptides should preferentially stabilize reverse this tendency. may explain inherited cause fAD provides molecular roadmap for development γ-secretase modulators, one most promising treatment strategies Alzheimer research. summary, we showcase power modern multiscale biochemical, protein-structural, elucidate complex mechanisms. categorized under: Structure Mechanism > Computational Biochemistry Biophysics Data Science Chemoinformatics