Fig. 5: PV-IN proteomic alterations in early stages of Aβ pathology in the 5xFAD model. | Nature Communications

Fig. 5: PV-IN proteomic alterations in early stages of Aβ pathology in the 5xFAD model.

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

Fig. 5

A Experimental outline for PV-CIBOP in 3-month-old 5xFAD mice. B IHC studies confirming PV-IN-specific biotinylation in WT and 5xFAD PV-CIBOP mice. C Flow cytometry analyses showing AAV-mediated targeting efficiency of PV-INs across experimental animals (n = 3/group; One-way ANOVA, p = 0.78; Data shown as mean ± SEM). D Aβ42 ELISA measurements from bulk cortex homogenates, confirming comparable Aβ42 levels across groups (n = 3 each for WT, FAD and Turbo WT, n = 4 Turbo 5xFAD, Data shown as mean ± SEM *p < 0.05, unpaired two-tailed T-test). E, F WB from bulk cortical tissue lysates and from SA-enriched samples showing robust biotinylation in PV-CIBOP compared to non-CIBOP mice. G PCA of MS data from SA-enriched proteomes: All PV-IN proteomes clustered away from control samples, and further distinction was observed between 5xFAD and WT PV-IN proteomes. H Heatmap representation of DEPs comparing WT/PV-CIBOP and 5xFAD/PV-CIBOP SA-enriched proteins. I PV-IN-specific DEPs minimally overlap with bulk tissue DEPs in 5xFAD and WT mice. J Top DEPs (showing at least 4-fold differential enrichment) comparing 5xFAD to WT PV-IN proteomes are shown (n = 3/group, mean ± SEM shown). K GSEA of DEPs comparing 5xFAD to WT PV-IN proteomes. L, M STRING protein-protein-interactions (PPI) within DEPs identified in Mitochondrial (L, increased in 5xFAD PV-IN) and Synaptic/Dendritic/Cytoskeletal (M, Decreased in 5xFAD PV-IN) ontologies. Thickness of edges indicates strength of known interactions. N Heatmap representation of DEPs comparing 5xFAD to WT PV-IN proteomes, limited to proteins encoded by genes with known genetic risk associations in AD (AD-MAGMA significance p < 0.05). O Enrichment of pro-resilience and anti-resilience proteins (from Yu et. al. PWAS study) within lists of DEPs (5xFAD vs. WT PV-IN proteomes). FDR 10% threshold is shown. P STRING PPIs of PWAS-nominated proteins positively associated with cognitive resilience (pro-resilience) that are decreased in 5xFAD PV-INs based on PV-CIBOP studies. Colors indicate shared functions and/or ontologies. Of these, proteins that are also selectively enriched in PV-INs as compared to Camk2a neurons (from CIBOP studies in Fig. 3) are highlighted (larger font, and bold). See Supplementary Fig. 6 and Supplementary Data 5 for related analyses. Source data provided as a Source Data file.

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