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. 2024 Jul 24;632(8026):858–868. doi: 10.1038/s41586-024-07606-7

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — a, The percentage of AD DEGs (pathologic diagnosis) overlapping with DEGs for neuritic plaques (neu. plaq.) and NFTs in each major cell type and region. b, Concordance of effect-sizes between neuritic plaque and NFT DEGs. Adjusted R² of log-transformed fold changes between neuritic plaque and NFT DEGs in each major cell type and region. c, The number of neuritic-plaque- or NFT-biased DEGs (≥3 DEGs for one of plaques or NFTs, and ≤2 for the other) for each major cell type or shared across 2+ cell types. d–i, The average effect sizes for NFTs and neuritic plaques for DEGs with biased differential effect sizes (d,f,h) and their respective functional enrichments (e,g,i), for DEGs shared across multiple cell types (d,e), in excitatory neurons (f,g) or in astrocytes (h,i). j, Enrichments (hypergeometric test) of pathology-biased DEGs in astrocyte modules. k, Enrichments (enr.) of AD DEGs in glial gene expression modules (*P_adj < 0.05, signed log₂[fold change], only significant modules are shown). l, Pearson correlation of module scores in each region with region-level pathology measures for glycolysis and oxidative phosphorylation modules in astrocytes, microglia and OPCs (^#P < 0.1). m, Core and selected diffuse plaque (diff. plaq.) DEGs in glial glycolysis-associated modules. n, Schematic of the glycolysis pathway, annotated by astrocyte diffuse plaque DEGs. Significant DEGs for diffuse plaques across all regions are indicated by asterisks. o,p, RNAscope validation of astrocyte energy metabolism DEGs in the AG of individuals with AD relative to control individuals without AD (pathologic diagnosis of AD). Representative images (left) show AQP4 transcripts (blue puncta) and ADCY8 (o) or PFKP (p) transcripts (red puncta). Scale bars, 20 μm (o and p). Quantification (right) was performed using unpaired two-tailed Student’s t-tests (ADCY8: n = 117 (non-AD) and n = 76 (AD) cells; PFKP: n = 43 (non-AD) and n = 40 (AD) cells). The dots represent individual cells, pooled from eight samples (four individuals; each had one PFC and one thalamus sample). Activ., activation; DAM, disease associated microglia; ox. phos., oxidative phosphorylation; resp., response.