Downregulation of FBXO2 is associated with Aβ aggregation, tau hyperphosphorylation and network impairment in human cortical neurons

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 that capture the molecular heterogeneity of the disease. In this study, we applied a systematic approach to identify potential transcriptomic promoters of sAD phenotypes by analysing single-nucleus RNA-seq data from the prefrontal cortex of early and late-stage AD patients. We experimentally tested 35 predicted genes using an Aβ aggregation assay in SH-SY5Y cells and functionally validated the shortlisted candidates in APPSwe and wild-type hiPSC-derived cortical neurons. Among the screened genes, FBXO2 knockdown increased measures consistent with amyloid aggregation in the cell models tested. In cortical neurons, FBXO2 knockdown was associated with increased Aβ oligomer secretion, elevated intracellular Aβ accumulation, tau hyperphosphorylation at disease-relevant sites (Ser396, Ser202/Thr205) and impaired electrophysiological function. Moreover, FBXO2 knockdown in wild-type neurons exposed to astrocyte-conditioned medium was accompanied by increased Aβ and tau phenotypes, while RNA sequencing revealed signatures of mitochondrial dysfunction. Together, these results illustrate a pipeline to prioritize candidate transcriptomic changes linked with AD-relevant states in human cortical neurons.