105 research outputs found

    Scoring and ranking of animal models with AD portrait; GFAP mutation differential gene expression results.

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    Scoring and ranking of over 500 models are compared with the AD portrait based on a hypergeometric test. Highest positive score represents the highest model match. Genes in the same direction are rewarded in scoring while genes in the opposite direction are penalized. Analysis also allows for identification of models that are most discordant with AD where patterns of genes are in the opposite direction. Differential gene expression of hippocampus and corpus collosum comparing GFAP mutation mouse model with control. (XLSX)</p

    Heat maps of congruent models with AD and common genes among models.

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    RRHO heatmaps [26] (human AD is X-axis) of additional congruent models with AD include: 5XFAD, APOE3 mutation with TBI; SOD1G93A strain, CK-p25 model, TDP-43 antisense treatment, MAPT mutation, infection with sporadic Creutzfeld-Jakob tissue, bulbectomized, PWScrm+/-, GNAS conditional KO, GRID2 KO, INSM1 KO, XBP1 KO, and CSTB KO (A). For the models shown and APP/PS1 and GFAP mutations, common genes with AD from at least 9 of the 16 models were identified (see S2 File) and ShinyGO [28] enrichment analysis was performed (B).</p

    UMAP plotting of models with human AD.

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    UMAP [27] was used to plot (A) all models and (B) just the top 50 models with the AD portrait using 5862 differentially expressed genes. A shorter distance (spatial proximity) of a model with human AD reflects a better match. The X- and Y-axes reflect arbitrary embedding dimensions for A and B. In (A), the top 50 models closely align with the AD portrait. AD portrait circle size was increased 10% and replotted in top surface to emphasize location. In (B), APP/PS1 (orange) and GFAP models (yellow-orange) were congruent with (close spatially to) the human AD (black) as were the 5XFAD (light green), SOD1G93A strain (blue), and the CK-p25 (blue/green) model.</p

    Congruent gene expression in APP/PS1 mice and human AD.

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    A: An RRHO heatmap [26] of the AD portrait (X axis) with the APP/PS1 mice (top ranked model) (Y axis) indicates a high matching of up-up and down-down genes (arrows). Color is–log transformed hypergeometric p-value showing the strength of the overlap as positive or negative enrichment. In X and Y axes the profiles of upregulated genes are shown in red and downregulated genes in blue (some clipping of highly significant downregulated genes occurred in the model). B: Enrichment analysis of common up and down regulated genes is shown using ShinyGO [28]. C: Congruent genes with the highest levels of protein-protein interaction (determined via STRING [29]) are plotted in Cytoscape [30]. Interactions are highlighted by lines. AD and model upregulated genes are shown in red and AD and model downregulated genes are shown in blue. Increased size of font for gene symbol reflects higher number of connections between genes. Common genes of interest include: GFAP, BDNF, GRIA2, GRIA1, GABRA1, GABRG2, SNAP25, and PTPRC.</p

    Scoring and ranking of animal models with multiple representations of human AD.

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    Human AD is represented by over 40 datasets, including meta-analysis from other studies, portraits for female AD and male AD, and individual datasets that are region and sex specific. Each of these is compared with the over 500 animal models and a ranking of the top models is provided based on the extent of similar gene expression patterns in the same direction. (XLSX)</p

    Top 20 models with highest congruence to human AD.

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    Overall rank from over 500 models and ranking is based on the hypergeometric score that rewards matching in same direction (up-up and down-down) while penalizing opposite patterns. Full scoring details provided in S1 File. Each of the top models was from mice except for Flinders and bulbectomize which were from rats. Model numbers in lower case “m” are from our previous [25] and current study while upper case “M” with upper case “A” added are from a different study [18] with original numbering used. GEO Omnibus or Synapse numbers are provided. Abbreviations: E, embryonic day; KO, knockout; cKO, conditional KO; CP, caudate putamen; sCreutzfeld-Jakob, sporadic Creutzfeld-Jakob; and TBI, traumatic brain injury. References (if available) are shown under genotype.</p

    Enrichment analysis of congruent genes in top models and AD portrait.

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    ToppCluster analysis [109] of genes from top ranking models that match human AD in the same direction. Common genes in multiple top models for AD are identified. (XLSX)</p

    Congruent gene expression in GFAP mice and human AD.

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    A: An RRHO heatmap [26] of the AD portrait (X axis) with the GFAP mutation mice (hippocampus; second ranked model) (Y axis) indicates a high matching of up-up and down-down genes (arrows). B: Enrichment analysis of common up and down regulated genes is shown using ShinyGO [28]. C: Congruent genes with the highest levels of protein-protein interaction (determined via STRING [29]) are plotted in Cytoscape [30]. Interactions are highlighted by lines. AD and model upregulated genes are shown in red and AD and model downregulated genes are shown in blue. Increased size of font for gene symbol reflects higher number of connections between genes. Common genes of interest include: GFAP, EGFR, TLR4, SNAP25, PTPRC, and SNCA.</p

    Common APP/PS1 and GFAP genes in the AD KEGG pathway.

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    Using analysis of the AD pathway within KEGG [47], twenty four common sites (in red bars) are found for where the same gene is perturbed in the same direction in the two genotypes and matches the AD KEGG pathway. Permission to use the copyrighted image was provided by KEGG [47]. Additional sites in the KEGG pathway are matched by genes only found in the same direction for APP/PS1 and the AD portrait (green star) or GFAP and the AD portrait (blue star). The common sites of action of GFAP and APP/PS1 are distributed across multiple sites in the AD pathway highlighting that while different mutations of different genes start the dysregulation, there is strong convergence of action. (PDF)</p

    Congruent gene expression in APP/PS1 and GFAP mice.

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    A: An RRHO heatmap [26] of the APP/PS1 (X axis) with the GFAP mutation mice (Y axis) indicates a high matching of up-up and down-down genes (arrows). B: Enrichment analysis of common up and down regulated genes is shown using ShinyGO [28]. C: Congruent genes with the highest levels of protein-protein interaction (determined via STRING [29]) are plotted in Cytoscape [30]. Interactions are highlighted by lines. Common upregulated genes are shown in red and AD and model downregulated genes are show in blue. Increased size of font for gene symbol reflects higher number of connections between genes. Common genes of interest include: GFAP, TLR4, PTPRC, ITGAM, and TYROBP. Note that the majority of highly connected genes between the two models are upregulated (in red). D: A Venn diagram [48] highlights overlapping genes in the AD portrait and the top two models.</p
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