Fig. 3: PV-IN molecular signatures are associated with neuropathology and cognitive resilience in humans. | Nature Communications

Fig. 3: PV-IN molecular signatures are associated with neuropathology and cognitive resilience in humans.

From: Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology

Fig. 3

A Summary of network-based analysis of human bulk brain proteomes derived from post-mortem frontal cortex samples from controls, AsymAD and AD cases, from ROSMAP and BANNER cohorts (adapted from Johnson et. al.)70. Protein co-expression modules (M1-42) are arranged in a circular manner. Dendrogram indicates module inter-relatedness. Module trait associations are arranged in layers: Cell type signatures with cell type-enrichment statistical significance (-log10 FDR; module-cognitive trait associations (MMSE and Global cognitive score); module-neuropathological trait associations (red: positive, blue: negative). B Modules that showed over-representation distinct neuronal markers (pan-excitatory, pan-inhibitory and IN classes, namely PV-IN, SST-IN and VIP-IN) are shown. Color indicates level of statistical significance of enrichment. C, D Comparisons of module eigenprotein abundances of M1 (C, pan-excitatory neuronal module) and M33 (D, PV-IN module) across controls, AsymAD and AD cases. Overall ANOVA p-value is shown and top neuronal class-specific proteins representative of M1 and M33 are highlighted. E, F Volcano plot representations of Module-trait correlations (X-axis: Bicor, Y-axis: -log10 p-value of correlation) for M1 (E) and M33 (F). Top correlated traits (including ApoE genetic risk based on allelic combinations of ApoE ε2, 3 and 4) are labeled. G Adjacency matrix analysis based on correlations between protein co-expression modules (ME vectors), Cell type abundance vectors (based on selected markers of 19 distinct brain cell types identified by sc/snRNAseq) and cognitive slope till time of death (Left: overall outline of the analytical plan). Right: Heatmap representation of Pearson’s correlation-based adjacency matrix. Cell type vectors and module ME vectors with representative ontologies of each ME, are shown on the left of the heatmap. Dendrogram on the right indicates relatedness among ME vectors, cell type vectors and cognitive slope, and revealed a cluster of PV-IN module M33, PV-IN vector, mitochondrial module M2 and M32, and cognitive slope (see Supplementary Data 3 for additional details). See Supplementary Data 3 and Supplementary Fig. 7 for related analyses. Image was created using BioRender.com.

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