Mitochondrial anomalies in induced pluripotent stem cells from Alzheimer’s disease cases with Presenilin 1 mutation

Presenilin 1 (PSEN1) is the most frequently mutated gene in early-onset sporadic and familial Alzheimer’s disease (FAD). The PSEN1 complex displays gamma-secretase activity and promotes cleavage of the C99-terminal fragment of the Amyloid Precursor Protein (APP) into the A42 peptide. PSEN1 is also involved in vesicle transport across ER and mitochondria in so called mitochondria associated membranes. We generated induced pluripotent stem cells (iPSCs) from 5 controls and 5 FAD cases carrying the PSEN1 A246E and L286V mutations. Unexpectedly, global gene expression profile analysis of FAD iPSCs revealed profound perturbation of mitochondrial, Golgi apparatus and ER pathways. PSEN1, APP and Nicastrin were highly expressed in iPSCs and PSEN1 localized to membrane-bound organelles. FAD iPSCs grown slower and showed elevated cell death together with abnormally high A42 secretion. Mitochondrial reactive oxygen species (ROS) were elevated in FAD iPSCs and treatment with a ROS scavenger significantly improved cell death, proliferation, and DNA damage. However, it could not improve the severe ATP deficit. Inhibition of gamma-secretase activity further exacerbated the overall FAD iPSC phenotype. Cortical neurons produced from the differentiation of FAD iPSCs showed Alzheimer’s pathology and TGFb pathway hyper-activation. PSEN1-mutant iPSCs may serve as a new model to perform genome-wide genetic screens and to study FAD pathophysiology and PSEN1 cellular function.