Fig. 6

Identifying transcriptomic signatures of selective vulnerability to Tau aggregation. a Funneling strategy to identify overlapping upregulated genes between our Tau-vulnerable cortical inhibitory hiPSC-neurons relative to Tau-resilient hypothalamic hiPSC-neurons and AT8-positive vs AT8-negative neurons from Otero-Garcia et al. [64]. The 2855 genes found to be upregulated in DIV19 cortical inhibitory hiPSC-neurons relative to hypothalamic hiPSC-neurons via bulk RNA-seq was narrowed to 628 gene candidates by looking for overlapping, upregulated genes from the single cell RNA-seq analysis of cortical inhibitory hiPSC-neuron gene expression relative to resilient hiPSC-neuron gene expression (hypothalamic, mDA, and spinal cord). The list of 628 genes upregulated in cortical inhibitory hiPSC-neurons relative to resilient hiPSC-neuron subtypes identified via bulk and single cell RNA-seq was then compared to the upregulated genes in AT8-positive human AD neurons from Otero-Garcia et al. (2022). The funneling strategy identified 116 genes for follow-up analyses. b Funneling strategy to identify overlapping downregulated genes between our Tau-vulnerable cortical inhibitory hiPSC-neurons relative to Tau-resilient hypothalamic hiPSC-neurons and AT8-positive vs AT8-negative neurons from Otero-Garcia et al. [64]. The 2353 genes found to be downregulated in DIV19 cortical inhibitory hiPSC-neurons relative to hypothalamic hiPSC-neurons via bulk RNA-seq was narrowed to 335 gene candidates by looking for overlapping, downregulated genes from the single cell RNA-seq analysis of cortical inhibitory hiPSC-neuron gene expression relative to resilient hiPSC-neuron gene expression (hypothalamic, mDA, and spinal cord). The list of 335 genes downregulated in cortical inhibitory hiPSC-neurons relative to resilient hiPSC-neuron subtypes identified via bulk and single cell RNA-seq was then compared to the downregulated genes in AT8 human AD neurons from Otero-Garcia et al. [64]. The funneling strategy identified 14 genes, too few to run follow-up enrichment analyses. c Venn diagram depicting the overlapping upregulated genes from our studies on tau-vulnerable hiPSC-neurons relative to tau-resilient hiPSC-neurons and from AT8-positive vs AT8-negative neurons from Otero-Garcia et al. [64] d Venn diagram depicting the overlapping downregulated genes from our studies on tau-vulnerable hiPSC-neurons relative to tau-resilient hiPSC-neurons and from AT8-positive vs AT8-negative neurons from Otero-Garcia et al. [64]. e Pathway enrichment analysis visualization for top 25 enriched GO terms for the 116 genes identified as upregulated in both vulnerable hiPSC-neurons relative to resilient hiPSC-neurons and in AT8-positive vs AT8-negative human AD neurons, enrichment p-value < 0.05. Lines between pathways represent overlapping genes between pathways. Number of genes refers to the number of differentially expressed genes from each GO term. Circle color represents adjusted p-value