Disruptions in cell‐cell communication in the entorhinal cortex of patients with Alzheimer’s disease and the 5xFAD mouse model

Abstract

AbstractBackgroundSingle‐cell sequencing has been instrumental in understanding cell‐type specific changes in Alzheimer’s disease (AD). While sequencing provides information about changes in individual cells, how these changes impact the interaction between cells is not as well‐defined. Understanding how the transcriptional and epigenetic changes that emerge during disease impact cellular communication will be critical in understanding key pathological changes that contribute to AD.MethodWe performed single‐nucleus RNA and ATAC‐seq (10x Multiome) to investigate gene expression and epigenetic regulation of cells in the entorhinal cortex (ENT) of 2‐month and 8‐month‐old 5xFAD and WT mice (n = 2 for each age, condition), and used publicly available single‐nucleus RNA‐seq data from the ENT of patients with and without AD. We used CellChat and the new package NeuronChat to explore how intercellular communication networks change between healthy and AD humans and mice. Based on these results, we then explored relationships between chromatin accessibility and gene expression for genes of interest.ResultWe observed changes in cell‐cell communication between AD and healthy samples in both mice and humans, particularly in the later stages of disease. The most prominent change was increased signaling from astrocytes to glutamatergic neurons in AD (Figure 1). This relationship included upregulation of neuroligin and ephrin‐A‐mediated signaling in AD, both previously implicated in synaptic regulation. In inter‐neuronal communications, the pathways most significantly disrupted in both human and mouse neurons were related to glutamatergic signaling. Multiple types of glutamate receptors were upregulated in both AD patients and 5xFAD mice in glutamatergic neurons, while GABAergic signaling did not appear to change. This finding is consistent with the hypothesis that glutamatergic neurons are hyperactive in AD and extends these observations by providing a potential mechanistic explanation of this phenomenon.ConclusionOur results indicate that in patients with AD and 5xFAD mice, dysfunction of the glutamatergic system is a prominent feature of pathogenesis and includes both inter‐neuronal signaling and communication with astrocytes. These results provide a series of testable hypotheses to explore the consequences of the transcriptional and epigenetic changes on the circuit dysfunction observed in AD.