Skip to main content
Fig. 9 | Molecular Neurodegeneration

Fig. 9

From: Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease

Fig. 9

Identification of AD-risk genes as key members of homeostatic, pro-inflammatory DAM and anti-inflammatory DAM modules. a Enrichment analysis of GWAS-identified AD risk genes in mouse microglial modules (1234 genes identified by MAGMA were used for this analysis [34]). An enrichment score of ≥1.96 (red line) corresponds to significant enrichment (p < 0.05). b-d AD GWAS hits specific to (b) Blue (homeostatic), (c) Yellow (anti-inflammatory DAM) and (d) Magenta (pro-inflammatory DAM) modules. Top 5 genes based on strength of disease association (X-axis: -log10 p-value) are highlighted by a gray silhouette and top 5 genes based on module membership (kME, Y-axis) are shown (also see Additional file 5: Table S5, Additional file 6: Table S6). e-h Analyses performed using quantitative proteomic data obtained from 47 post-mortem human frontal cortices (BLSA, n = 20 confirmed AD cases with cognitive decline, n = 13 controls without any AD pathology and n = 14 cases with AD pathology without cognitive symptoms). e Overlap of mouse modules [Blue/homeostatic, Yellow/anti-inflammatory DAM, Magenta/pro-inflammatory DAM, Purple (homeostatic), Cyan (IL4-upregulated module) and Midnightblue (LPS-upregulated module)] with human protein modules by hypergeometric one-tailed Fisher-exact test. Color intensity indicates strength of significance after Benjamini-Hochberg FDR correction. Strongest FDR-corrected p-values (0.075) were seen for overlap between Yellow and Magenta mouse microglial modules with M2 (unadjusted p = 0.0013), M4 (unadjusted p = 0.0014) and M35 (unadjusted p = 0.0014) human proteomic modules. Y-axis: Mouse WGCNA modules; X-axis: Protein BLSA modules. Correlations between BLSA modules with CERAD and Braak neuropathological grades of AD are shown. f Distribution of mouse microglial module hub genes (kME ≥ 0.90) in human BLSA AD proteome. g Comparison of aggregate expression of Magenta, Yellow and Blue mouse microglial modules in control, asymptomatic AD and clinical AD. Modules with ≥5 hub genes (kME ≥ 0.8) were included. Median module expression was calculated and compared across groups. h Normalized protein expression data of top three proteins from the pro-inflammatory Magenta module (CD44, Bst2 and Nampt) are shown

Back to article page