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SINGLE-NUCLEI TRANSCRIPTOMIC ANALYSES OF HEALTHY AND ALZHEIMER’S DISEASE (AD) HUMAN BRAINS REVEAL CHANGES IN NEURON-MICROGLIA CELLULAR CROSSTALK PATTERNS
Abstract
Aims
Investigate changes in brain cellular crosstalk patterns between healthy and AD individuals.
Methods
We generated single-nuclei transcriptomic profiles (snRNA-seq) of parietal lobes from 67 donors, representing neuropathological-free controls and AD cases from pre-symptomatic, early, mid and late disease stages. We estimated cellular crosstalk patterns among the brain cell types based on the expression of known ligand-receptor pairs.
Results
We analyzed ~294K high-quality nuclei and identified six major cell populations. We observed changes in cellular crosstalk patterns between healthy and AD individuals, with the largest involving microglial interactions (increased in AD, OR=1.31, p=8.94e-11). Cellular interactions directly involving AD-related genes as either the receptor or the ligand were enriched for neuron-microglia pairs (OR=2.74, p=4.41e-15), 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 AD-related interactions involving microglia when comparing pre-symptomatic and AD individuals, including TREM2-semaphorin (neuron-microglia, 4.38-fold increase), suggesting correlation with pathological burden. Another subset of microglia interactions, including HLADPB1-TNFSF13B (astrocyte-microglia, 4.67-fold increase), had increased frequency only in AD-risk variants carriers, suggesting these variants lead to pathological upregulation of these interactions. We compared interactions involving AD genes to interactions involving genes prioritized by GWAS for five neurological conditions. We identified shared and specific cellular crosstalk patterns across neurological conditions, consistent with distinct disease mechanisms.
Conclusions
Our work reveals the role of cellular crosstalk in AD biology and identifies disruptions in neuron-microglia interactions as an important component of AD pathology.