Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations

The enzyme complex gamma-secretase generates amyloid beta-peptide (A beta), a 37-43-residue peptide associated with Alzheimer disease (AD). Mutations in presenilin 1 (PS1), the catalytical subunit of gamma-secretase, result in familial AD (FAD). A unifying theme among FAD mutations is an alteration in the ratio A beta species produced (the A beta 42/A beta 40 ratio), but the molecular mechanisms responsible remain elusive. In this report we have studied the impact of several different PS1 FAD mutations on the integration of selected PS1 transmembrane domains and on PS1 active site conformation, and whether any effects translate to a particular amyloid precursor protein (APP) processing phenotype. Most mutations studied caused an increase in the A beta 42/A beta 40 ratio, but via different mechanisms. The mutations that caused a particular large increase in the A beta 42/A beta 40 ratio did also display an impaired APP intracellular domain (AICD) formation and a lower total A beta production. Interestingly, seven mutations close to the catalytic site caused a severely impaired integration of proximal transmembrane/hydrophobic sequences into the membrane. This structural defect did not correlate to a particular APP processing phenotype. Six selected FAD mutations, all of which exhibited different APP processing profiles and impact on PS1 transmembrane domain integration, were found to display an altered active site conformation. Combined, our data suggest that FAD mutations affect the PS1 structure and active site differently, resulting in several complex APP processing phenotypes, where the most aggressive mutations in terms of increased A beta 42/A beta 40 ratio are associated with a decrease in total gamma-secretase activity. (C) 2014 The Authors. Published by Elsevier B.V.