Cell‐type specific selective vulnerability to pathological tau in Alzheimer's disease

Background Region‐specific neuronal subpopulations known to be selectively vulnerable to Tau pathology, as characterized in our previous work (Fu et al., 2019), were identified across several public single‐nucleus RNA sequencing datasets from non‐diseased human in order to derive putative properties and mechanisms that drive vulnerability. Methods We analyzed datasets from the Allen Brain Institute (Hodge et al., 2019), Broad Institute (Habib et al., 2017), and Polo group (Grubman et al., 2019). After QC, dimensionality reduction, and clustering, vulnerable and invulnerable neuronal subpopulations were identified using anatomical metadata and marker genes. Differential expression between subpopulations were performed using the Wilcoxon test, while differential pathway analysis was carried out using the GSVA algorithm. Result We were able to identify putative subpopulations across a range of presumed vulnerability as defined by classical pathological staging. Several themes emerge from differential pathway analysis of these subpopulations in various comparisons, including those related to vesicle‐mediated exocytosis activity and synaptic plasticity. Following further drilling down of these pathways for their association with vulnerability, pathways will be systematically screened in a model system measuring Tau aggregation. Conclusion Extensive pathway analysis of neuronal subpopulations selectively vulnerable to Tau pathology in human single‐nucleus RNA sequencing data reveal significant heterogeneity between neurons that may be responsible for driving pathological status.