A unique subpopulation of wild-type neurons recapitulating familial Alzheimer's disease phenotypes.

Mutations in the genes encoding APP, Presenilin-1 (PSEN1), and PSEN2 result in early-onset Alzheimer's disease (AD). Previous studies, using iPSC-derived neurons and/or knock-in mice, elucidated the characteristics of neurons expressing familial AD (fAD) mutations. Here, we employ biochemical and state-of-the-art fluorescence imaging assays and report the discovery of a unique subpopulation of wild-type neurons strikingly recapitulating key phenotypes previously identified in the fAD neurons, including the favored production of longer over shorter β-amyloid (Aβ) peptides, endo-lysosomal abnormalities, and increased vulnerability phenotypes in response to toxic insults. Importantly, mechanistic studies define inefficient γ-secretase and impaired endo-lysosomes as the upstream events of increased neuronal susceptibility. This discovery of the unique population of neurons with disease phenotypes would open a new avenue to develop novel therapeutics targeting neuronal vulnerability.