Integrated analysis of spatial and single-cell profiles reveals cell type–specific regulation of synaptic plasticity in human brain aging

Aging is intricately linked to neurodegenerative diseases and cognitive decline, with the prefrontal cortex (PFC) playing a critical role in higher cognitive functions such as decision-making and memory. Despite advances in transcriptomic profiling, our understanding of cell type-specific and spatial regulatory mechanisms in brain aging remains incomplete. This study integrates single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq), and spatial transcriptomics to uncover molecular and cellular alterations associated with PFC aging. We analyzed data from 51 healthy human PFC samples, categorized into young, middle-aged, and elderly groups. Differential gene expression (DEG) analysis identified 3932 aging-related DEGs, among which excitatory neurons exhibited the most significant molecular alterations. This study suggests that EGR1 may serve as a potential key regulator of synaptic plasticity during aging; our findings indicate that reduced chromatin accessibility in the excitatory neurons of elderly individuals may subsequently lead to the downregulation of EGR1. Spatial transcriptomics revealed enriched EGR1 expression in specific cortical layers and its progressive decline with age. Furthermore, EGR1 targets-including YWHAZ, CTNNB1, and CDC42-were implicated in synaptic plasticity pathways such as the Wnt and Hippo signaling pathways. These findings suggest that EGR1 dysfunction may contribute to synaptic deficits and cognitive impairment during aging. This study provides a comprehensive view of cell-type-specific and spatial molecular mechanisms underlying PFC aging, highlighting EGR1 as a potential biomarker and therapeutic target for age-related cognitive decline. Our integrative approach advances the understanding of brain aging and lays the groundwork for anti-aging interventions.