Mariana Acquarone De Sá Lopes (United States of America)
The Ohio State University Wexner Medical Center NeuroscienceAuthor Of 1 Presentation
SYSTEMATIC CHARACTERIZATION OF BRAIN CELLULAR CROSSTALK SIGNALING NETWORKS IN ALZHEIMER’S DISEASE USING SINGLE-NUCLEUS TRANSCRIPTOMICS REVEALS A NOVEL ROLE FOR SEMA6D IN TREM2-DEPENDENT MICROGLIAL ACTIVATION
Abstract
Aims
We used single-nucleus transcriptomic profiles from healthy and Alzheimer's disease (AD) human brains to identify cellular crosstalk interactions that can regulate AD pathology.
Methods
In this study we generated single-nuclei transcriptomic profiles (snRNA-seq) of parietal lobes from 67 donors, representing neuropathological-free controls and AD cases. We identified patterns of ligand-receptor gene expression across cell type pairs and their corresponding transcriptional states using CellPhoneDB. Upon identification of neuron-microglia enriched ligand-receptor pairs, we generated human iPSC-derived microglia (iMG) to assess specific microglia receptor function.
Results
We analyzed ~294K high-quality nuclei and identified six major cell populations. We observed changes in cellular crosstalk patterns between controls and AD, with the largest involving microglial interactions. Cellular interactions directly involving AD-related genes as either the receptor or the ligand were enriched for neuron-microglia pairs, and the majority (64.9%) codified for microglial cell membrane receptors, supporting the role for these cells in AD. We observed an increase in the frequency of a subset of interactions involving AD-related genes in microglia when comparing pre-symptomatic and AD individuals, suggesting a correlation with pathological burden. This included an interaction between the AD risk gene TREM2 and Semaphorin 6D (Sema6D). We used human iPSC-derived microglia to explore this interaction in vitro and demonstrated that Sema6D promotes microglial phagocytosis and cytokine release in a TREM2-dependent manner.
Conclusions
This study reveals the role of cellular crosstalk in AD biology and identifies disruptions in neuron-microglia interactions as an important component of AD pathology. Specifically we identify cellular crosstalk between the microglia receptor TREM2 and Sema6D. We demonstrate that Sema6D can regulate microglial function in a TREM2-dependent manner and could serve as a potential therapeutic target.