HETEROGENOUS SPATIOTEMPORAL GLIA-NEURON COMMUNICATIONS DURING PROGRESSION OF THE ALZHEIMER’S DISEASE (AD)

The pathogenic mechanisms of AD are complex, and the disease has a prolonged asymptomatic phase, making early diagnosis and interventions possible and necessary. In addition to the degenerating neurons, the glial cells in the tissue microenvironment play essential roles in regulating the AD pathogenesis, leading to functional circuit impairment and the cognitive deficits. Therefore, modulating the cell-cell communications between the glia and neurons via the ligand-receptor-based signaling pathways is emerging to be a promising strategy for AD treatment. We therefore performed the single cell spatial transcriptomic sequencing of AD mouse brain at different progressing stages, and built a comprehensive cell-cell communication atlas with newly developed AI algorithm and expanded ligand-receptor pools. By analyzing neuronal heterogeneity in their cell-cell communication patterns and resilience to AD-induced cell death, we discovered specific glia-neuron communication patterns. We identified one unique subtype of astrocytes specifically co-localize and communicate with hippocampal neurons with the best survivability throughout the course of AD progression. In contrast, a specific subtype of microglia co-localizes and communicates with neurons dying significantly at late AD stage. Finally, macrophages expand extensively at late AD stage with drastic neuronal loss and cognitive defects. By comparing and contrasting these heterogenous spatiotemporal glia-neuron communications, we discovered a list of ligand-receptor pairs that might function to regulate neuronal cellular state during AD pathogenesis. Importantly, functional validations have identified several novel pathways that can be targeted to prevent neurodegeneration and enhance cognition functions. Together, our study provides new targets and strategies for early diagnosis and intervention of AD.