Alzheimer’s disease models in iPSC-derived glutamatergic neurons show increased secretion of pathogenic amyloid beta peptides

Alzheimer’s disease (AD), a complex, multifactorial neurodegenerative disease, is challenging to study in vitro due to a lack of physiologically relevant models. ioGlutamatergic Neurons carrying the PSEN1 M146L and APP V717I mutations secreted significantly more Aβ42 compared to their wild type control, showing higher Aβ42:40 ratios. A clear correlation between genotype and Aβ42:40 ratios was observed, as wild type, heterozygous and homozygous mutants showed a stepwise increase in Aβ42 production relative to Aβ40. ioGlutamatergic Neurons APP KM670/671NL secreted significantly more Aβ38, Aβ40, and Aβ42 than their wild type control, but the Aβ42:40 ratio did not increase, as expected.

ioGlutamatergic Neurons with mutations in PSEN1 or APP recapitulate the increase in Aβ42 secretion observed in Alzheimer’s patients, demonstrating their validity as an in vitro model to study AD and for the discovery of drugs targeting the pathogenic Aβ pathway.