Intercellular signaling and synaptic deconstruction uncovered by single-cell and spatial transcriptomics in an AD tauopathy model

Alzheimer's disease (AD) is the leading cause of dementia in elderly individuals worldwide; however, all the mechanisms leading to its onset and progression are not fully understood. Here, we report single-cell multiome and spatial transcriptomics analysis of the brain in a transgenic rat model of human-like tauopathy. In this advanced transgenic model, we have identified new markers of a tau-driven AD pathology and provided single-cell evidence for previously known genes implicated in AD. Our findings reveal how tau pathological hyperphosphorylation and aging alter ligand-receptor communication, transcription factor regulatory networks, and specific cellular networks. Notably, we found intriguing changes in cell communication involving glutamatergic transmission and netrin signaling as a consequence of the tauopathy. Overall, this study reinforces the concept of synaptic dysfunction as a hallmark of AD and highlights potential targets for future mechanistic investigations or novel therapeutic strategies. Overall design: Multiome-seq: Joint snRNA-seq and scATAC-seq performed using 10x Genomics platform. Spatial-seq: performed using 10x Genomics Visium platform. Both consist of AD model rat hippocampal or cortex tissues from 10 month and 20 months old samples and wild-type counterparts.