Analysis of changes in inter-cellular communications during Alzheimer's Disease pathogenesis reveals conserved changes in glutamatergic transmission in mice and humans
Analysis of system-wide cellular communication changes in Alzheimer's disease (AD) has recently been enabled by single nucleus RNA sequencing (snRNA-seq) and new computational methods. Here, we combined these to analyze data from postmortem human tissue from the entorhinal cortex of people with AD and compared our findings to those from multiomic data from the 5xFAD amyloidogenic mouse model at two different time points. Using the cellular communication inference tool CellChat we found that disease-related changes were largely related to neuronal excitability as well as synaptic communication, with specific signaling pathways including BMP, EGF, and EPHA, and relatively poor conservation of glial-related changes during disease. Further analysis using the neuron-specific NeuronChat revealed  changes relating to metabotropic glutamate receptors as well as neuronal adhesion molecules including neurexins and neuroligins. Our results that cellular processes relating to excitotoxicity are the best conserved between 5xFAD mice and AD suggest that excitotoxicity is the main common feature between pathogenesis in 5xFAD mice and people with AD. Overall design: Multiome-seq: the entorhinal cortex region was extracted from the brains of WT and 5xFAD mice at 2 months and 8 months of age. Single nuclei were isolated and snRNA-seq and snATAC-seq libraries were prepared using the 10x Multiome kit