Structural Impacts of Familial Alzheimers Disease (FAD) Mutations on Amyloid Precursor Protein (APP) Cleavage by -secretase Subunits APH1A and PSEN1

This paper surrounds the question of how Familial Alzheimers Disease (FAD) mutations in the C99 fragment of the amyloid precursor protein (APP) affects its structure, as well as the -secretase subunits PSEN1 and APH1A. These interactions are critical for determining the production of amyloid- (A) peptides in the -processing pathway, particularly the ratio of A42 to A40, which is implicated in Alzheimers pathology. While many FAD mutations in APP are known to increase A42 production, the precise structural mechanism by which these mutations disrupt C99s interaction with -secretase, and how that disruption leads to altered cleavage patterns, has not been well characterized. Previous studies have identified the correlation between mutations and disease progression, but few have explored the structural and binding changes at a molecular level using predictive modeling. From Alpha Fold-2 and RMSD analysis in PyMOL, several mutations like V715A, T714I, or V717G, were found to significantly alter the structure of C99, which subsequently also changed the way it bound to PSEN1 or APH1A. Conversely, other mutations like V717I or I716V were found to have minimal structural impact. These results suggest that the destabilization of C99 and its altered binding may prevent -secretase from completing the necessary sequential cuts, which provides an explanation for the increased A42:A40 ratios in patients who have these mutations.