Intercellular signaling and synaptic deconstruction uncovered by single-cell and spatial transcriptomics in an AD tauopathy model
Jeff Ji, Brian L. Giles, Surjyadipta Bhattacharjee, Marie‐Audrey I. Kautzmann, Alasdair P. Masson, Sonia Do Carmo, A. Claudio Cuello, Nicolás G. Bazán
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia in elderly individuals worldwide; however, all mechanisms leading to disease onset and progression are not well understood. Here, we report brain single-cell multiome and spatial transcriptomics in a transgenic rat model of human-like tauopathy. We have identified new markers of tau-driven AD pathology and provided single-cell evidence for genes implicated in AD. Our findings reveal how tau 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 taupathy consequence. Overall, this study reinforces the concept that synaptic dysfunction is a critical early event in AD and highlights potential targets as potential therapeutic strategies. Single-cell multiome and spatial transcriptomic analysis reveals new disease markers in the hippocampus implicated in both early and late stage of a tauopathy model of Alzheimer’s Disease.