Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta

Familial Alzheimer's disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by gamma -secretase, increasing the proportion of longer amyloidogenic amyloid-beta (A beta) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the A beta secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased A beta 42:40 ratio relative to controls, yet displayed varied signatures for A beta 43, A beta 38, and short A beta fragments. We propose four qualitatively distinct mechanisms behind raised A beta 42:40. (1) APP V717I mutations alter gamma -secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced gamma -secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced gamma -secretase carboxypeptidase-like activity. These data support A beta mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD.