A human neuronal model of sporadic Alzheimer’s disease induced by FBXO2 downregulation shows Aβ aggregation, tau hyperphosphorylation and functional network impairment

Sporadic Alzheimer’s disease (sAD) arises from a complex interplay between genetic and environmental factors that remains poorly understood, making it challenging to develop accurate cell models. To address this problem, by hypothesing that the early disease sAD states can be characterised by transcriptomic fingerprints, we assessed the effect on Aβ aggregation in human neuroblastoma cells a set of genes obtained by analysing snRNA-seq data from post-mortem AD patients. We then validated the most effective genes in human iPSC-derived cortical neurons, and selected FBXO2 , a gene encoding a subunit of the ubiquitin protein ligase complex SCF, for further analysis. We found that early downregulation of FBXO2 in human iPSC-derived cortical neurons resulted in Aβ aggregation, tau hyperphosphorylation, and structural and functional neuronal network impairment. Based on these results, we report a neuronal sAD model ( FBXO2 KD sAD) that recapitulates a set of molecular hallmarks of sAD. We suggest that this strategy can be expanded towards the generation of panels of preclinical stem cell-derived models that recapitulate the molecular complexity of the broad spectrum of AD patients.