ABSTRACT: Alzheimer’s disease (AD) disrupts neurogenesis and neuronal differentiation, processes critical for cognitive function. This study investigates transcriptional and regulatory changes during neuronal differentiation under the influence of amyloid-beta (Aβ) peptide using scRNA-seq and scATAC-seq approaches. Neuronal differentiation trajectories showed three distinct groups of differentially expressed genes (DEGs). Notably, while some neurogenesis-related genes like VIM, MAPT, STMN2, and SLC17A6 were unaffected by Aβ, others, such as PAX6, NEFL, NEFM, and CALB1, displayed significant alterations, particularly in transitions to mature neuronal states. Functional enrichment analysis highlighted disruptions in ATP synthesis, oxidative phosphorylation, synaptic signaling, and cytoplasmic translation. Regulatory transcription factors (TFs) such as EGR1, GATA2, PAX6, and SOX2 were also implicated in these changes. Translational characterization revealed that the gene expression changes observed in the Aβ condition partially aligned with dysregulated gene patterns in hippocampal tissue from AD patients. Differential analysis across stages indicated that mature neuronal differentiation stages exhibited stronger concordance with AD-related gene expression. To understand the role of chromatin accessibility, scATAC-seq analysis identified dysregulation in gene regulatory networks (GRNs) driven by key TFs such as ASCL1, HOXB2, POU2F2, and ONECUT2. Notably, regulons promoting neurogenesis in control conditions were impaired or delayed under Aβ exposure, with regulons specific to mature neuronal transitions emerging only in the presence of Aβ. Functional analysis of these regulons revealed enrichment for pathways associated with differentiation, neuron migration, and synaptic regulation, suggesting Aβ-mediated disruption of neurogenesis-associated regulatory programs. In summary, this study highlights Aβ-induced transcriptional and regulatory disruptions during neuronal differentiation, linking these changes to AD pathology. It underscores the importance of transcriptional and epigenetic regulation in understanding AD and provides insights into how Aβ interferes with neurogenic processes critical for neuronal maturation and function.
