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A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease

Nature Neuroscience volume 29, pages 25–39 (2026)Cite this article

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Abstract

Alzheimer’s disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer’s disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4–10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence. CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies.

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Fig. 1: Generation and characterization of DS-WT and DS-A455D hiPSC-derived PMPs, and tau-induced cytotoxicity on DS-WT and DS-A455D microglia.
Fig. 2: DS-A455D microglia give rise to a distinct microglial subpopulation in response to DSAD-tau S1 fraction in chimeric brains.
Fig. 3: DAM clusters identified from DS-A455D microglial chimeric brains receiving injection of Control or DSAD tau.
Fig. 4: CSF2RB A455D mutation protects DS microglia against senescence.
Fig. 5: DS-A455D microglia protect neuronal functions in response to DSAD-tau S1 fraction.
Fig. 6: CSF2RB A455D mutation resilience is independent of trisomy 21.
Fig. 7: Control A455D microglia replace Control WT microglia in response to pathological tau.

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Data availability

The RNA-seq, scRNA-seq and whole-genome sequencing datasets generated in this study have been deposited at the NCBI Gene Expression Omnibus (accession no GSE252238) and are publicly available as of the date of publication. Source data are provided with this paper.

Code availability

This paper does not report any original code.

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Acknowledgements

We thank the UCI-ADRC and the BrightFocus Foundation for providing us with the DSAD and Control human brain tissues. We thank P. Xie (Rutgers University) for assistance with flow cytometry and K. Kwan (Rutgers University) for help with scRNA-seq library preparation. We also thank A. Kumar and K. Aluru from the Jiang laboratory for their assistance with immunohistochemistry, and F. Chanut for editorial assistance. This work was in part supported by grants from the NIH (grant nos. R01NS102382, R01NS122108 and R01AG073779 to P.J.). M.J. was supported by a postdoctoral fellowship award from the New Jersey Department of Health (no. CAUT24DFP004). A.V.P. was supported by a graduate trainee T32 fellowship award from the Training in Translating Neuroscience to Therapies program at Rutgers University (no. T32NS115700). Y.L. was supported by NIH grant no. R01NS110707. Additional support came from the NIH (grant nos. R01AG064579 and RF1NS128800), the JSRM Foundation, the BrightFocus Foundation (BFF17-0008) and the Alzheimer’s Association to S.F, as well as UCI-NIH funding (NIH/National Institute of Aging grant no. P30AG066519) supporting the UCI-ADRC.

Author information

Authors and Affiliations

  1. Department of Cell Biology and Neuroscience, Rutgers University-New Brunswick, Piscataway, NJ, USA

    Mengmeng Jin, Ziyuan Ma, Rui Dang, Haiwei Zhang, Rachael Kim, Ava V. Papetti & Peng Jiang

  2. Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Center for Translational Science, Florida International University, Port St. Lucie, FL, USA

    Haipeng Xue & Ying Liu

  3. Department of Pathology and Laboratory Medicine, Department of Neurology, University of California, Irvine, CA, USA

    Jesse Pascual & Elizabeth Head

  4. Institute for Stem Cell and Neural Regeneration, School of Pharmacy, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China

    Hanwen Yu & Yan Liu

  5. Center for Systems and Therapeutics and the Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, San Francisco, CA, USA

    Steven Finkbeiner

  6. Departments of Neurology and Physiology, University of California, San Francisco, CA, USA

    Steven Finkbeiner

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  1. Mengmeng Jin
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Contributions

M.J. and P.J. designed the experiments and interpreted the data. M.J. carried out most of the experiments with technical assistance from H.Z. and R.D. Z.M. performed the RNA-seq data analyses and assisted with the interpretation of the sequencing data. Yan Liu and H.Y. performed the donor assignment of the microglia scRNA-seq analyses. R.D. performed the electrophysiological recordings. J.P. and E.H. prepared the human brain tissue extracts. Ying Liu and H.X. generated the CSF2RB A455D DS and CAGG hPSC lines. R.K. assisted with immunostaining and the Imaris analysis. A.V.P. assisted with the flow cytometry experiment. S.F. and E.H. provided critical suggestions to the study. P.J. conceived the study, directed the project and wrote the manuscript together with M.J. and input from all coauthors.

Corresponding author

Correspondence to Peng Jiang.

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Competing interests

P.J. and M.J. have filed a patent related to this work (US patent application no. 63/563,637). The other authors declare no competing interests.

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Nature Neuroscience thanks Li Gan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Generation and characterization of A455D hiPSC.

a-b, Schematic of targeting CSF2RB WT or A455D mutant to intron 10. Donor sequences of both WT and A455D mutant are mammalian codon optimized. P2A is the self-cleaving peptide that allows for simultaneous, separate protein expression of EGFP (Panel a) or mRuby (Panel b) cassette. Puro, puromycin resistance fragment; SA, splice acceptor. c-f, PCR identification and Sanger sequencing verification of targeted hiPSC clones. Genomic DNA extracted from single clones was examined by PCR for identification of correctly targeted alleles (c, d), which were subsequently verified by Sanger sequencing (e, f).

Source Data

Extended Data Fig. 2 scRNA-seq analysis of DS-WT and DS-A455D microglia in response to DSAD-Tau S1 fraction in chimeric mice.

a-b, Representative images of hTMEM119+hN+ and Ki67+hN+ in DS-WT and DS-A455D chimeric mice. Scale bar: 20 μm and 10 μm in the original and enlarged images, respectively. c-d, Quantification of the percentage of hTMEM119+ and Ki67+ in hN+ cells from DS-WT and DS-A455D chimeric mice (Data represent both sexes combined, n = 4 mice per group), Student’s t-test, NS, not significant. Data are presented as mean ± SEM. e, Flow cytometry analysis of p-STAT5 expression in DS-WT and DS-A455D groups. f, Quantification of p-STAT5 expression in DS-WT and DS-A455D groups (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, #P = 0.0286. Data are presented as mean ± SEM. g, Representative images of sagittal brain sections showing the distribution of AT8+ puncta at two months post-injection. Scale bar: 200 and 50 μm in the original and enlarged images, respectively. h, Representative images of immunohistochemistry staining with AT8 from control-Tau and DSAD-Tau injected chimeric mouse. Scale bar: 10 and 5 μm in the original and enlarged images, respectively. i, Quantification of the percentage of AT8+ cells in the hippocampus (Data represent both sexes combined, n = 4 mice per group). Arrowheads indicate AT8+ staining. Data were analyzed by a two-tailed unpaired t-test, *P < 0.05. Data are presented as mean ± SEM. j, Representative images of Ki67+hN+ in DS-WT-DSAD-Tau and DS-A455D-DSAD-Tau chimeric mice. Scale bar: 20 μm and 10 μm in the original and enlarged images, respectively. k, Quantification of the percentage of Ki67 in hN+ cells from DS-WT-DSAD-Tau and DS-A455D-DSAD-Tau chimeric mice (Data represent both sexes combined, n = 4 mice per group), Data were analyzed by a two-tailed unpaired t-test, #P < 0.05. Data are presented as mean ± SEM.

Source Data

Extended Data Fig. 3 scRNA-seq analysis of DS-WT and DS-A455D microglia in response to DSAD-Tau S1 fraction in chimeric mice.

a, A schematic diagram showing the design of the scRNA-seq experiment. b, Violin plots representing the quality control parameters (gene count, UMI counts, and mitochondrial gene percentage) of the scRNA-seq dataset in Cont- and DSAD-Tau-treated groups. Violin plots showing the distribution of detected RNA features (nFeature_RNA) across different clusters (0-9). c, Split UMAP plots showing microglial subclusters (clusters 0-9) from 4 experimental groups. d, Heatmap showing cluster-specific marker gene expression. e, Violin plot showing 20 canonical microglia marker gene expression levels in each microglial subcluster. f, Heatmap showing cosine similarity scores calculated between clusters. g, Violin plot showing canonical DAM marker gene expression levels in each microglial subcluster. h, UMAP plots colored by features of DAM scores, phagocytic microglia scores, FTL, and FTH1 expression. Schematics in a was created using Biorender. Jin, M. (2025) https://BioRender.com/w18g951. i, Barplot showing the proportion of cell cycle phases between clusters. j, Barplots showing the proportion of cells in each cluster between experimental groups. k, UMAP representation of all inferred trajectories of DS-A455D microglia in response to control-Tau and DSAD-Tau. l, Dynamic plots showing additional selected gene expression profiles across inferred pseudotime in lineage 1 and lineage 3. Dots in the plots are cells colored by microglial subclusters.

Source Data

Extended Data Fig. 4 scRNA-seq analysis of DS-A455D microglia in response to DSAD-Tau S1 fraction.

a, Schematic of the scRNA-seq experimental design for two 10-month-old samples. b, Violin plots showing quality control parameters for the scRNA-seq dataset. c, Bar plots showing the distribution of cells across clusters in each sample. d, UMAP plot of microglial clusters (clusters 0–7) from the two 10-month-old samples. e, Dot plot showing the expression levels of human microglial marker genes across clusters. f, Ridgeline plot of DAM score distributions across clusters. g, Heatmap showing cluster similarity between 4-month-old and 10-month-old samples, with Jaccard scores representing the proportion of overlapping genes. Statistical significance of overlap was determined via Fisher’s exact test. h, Scatter plot of significantly differentially expressed genes in each cluster. i, Bar plot of selected protective GO BP terms from enrichment analysis of the top 100 positive significant marker genes (adjusted p-value < 0.05, ranked by average LogFC). j, Bar plots comparing proportions of homeostatic microglia and DAM between 10-month-old and 4-month-old samples. k, GO enrichment analysis of positive marker genes for each cluster, no IFN-related terms are enriched. l, UMAP plots comparing the density of IFN α/β-responsive gene-expressing cells between 10-month-old and 4-month-old samples. Schematics in a was created using Biorender. Jin, M. (2025) https://BioRender.com/59efcbt.

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Extended Data Fig. 5 CSF2RB A455D mutation protects DS microglia against senescence.

a, Ridgeline and box plots showing the senescence score in DS-WT and DS-A455D microglia under control-Tau and DSAD-Tau conditions. Wilcoxon test, ***P < 0.001. b, GSEA plot showing enrichment of interferon genes in DS-A455D-DSAD-Tau and DS-WT-DSAD-Tau groups. c, qPCR analysis of IRF8 and IFITM3 mRNA expression in chimeric mice at month 4 (n = 4-5 mice per group). Student’s t-test, *P = 0.0286, **P = 0.0079. Data are presented as mean ± SEM. d, Representative images of anti-hCD45 (green) and anti-p21 staining (red) in DS-WT-DSAD-Tau and DS-A455D-DSAD-Tau groups; Arrows indicate p21+ and/or hCD45+ staining. Scale bar, 10 and 5 μm in the original and enlarged images, respectively. e, Quantification of the percentage of p21 in hCD45+ cells (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286. Data are presented as mean ± SEM. f, Representative raw fluorescence super-resolution and 3D surface rendered images showing images of colocalization of LAMP1+ and LC3B in hCD45+ microglia in 4-month-old DS-WT-DSAD-Tau and DS-A455D-DSAD-Tau chimeric mice. Scale bars: 5 μm and 3 μm in the original and enlarged images, respectively. g, Quantification of LAMP1+ puncta in hCD45+ microglia in 4-month-old DS-WT-DSAD-Tau and DS-A455D-DSAD-Tau chimeric mice (Data represent both sexes combined, n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, **P = 0.0079. Data are presented as mean ± SEM. h, Quantification of LC3B+ puncta in hCD45+ microglia in 4-month-old DS-WT-DSAD-Tau and DS-A455D-DSAD-Tau chimeric mice (Data represent both sexes combined, n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, **P = 0.0079. Data are presented as mean ± SEM. i, Quantification of colocalization of LAMP1+ and LC3B in hCD45+ microglia in 4-month-old DS-WT-DSAD-Tau and DS-A455D-DSAD-Tau chimeric mice (Data represent both sexes combined, n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, **P = 0.0079. Data are presented as mean ± SEM.

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Extended Data Fig. 6 AC-4–130 treatment abolishes the protective effects of the CSF2RB A455D mutation on human microglia.

a, Representative images showing colocalization of hCD45+ and Ferritin+ staining in DS-A455D-DSAD-Tau+vehicle and DS-A455D-DSAD-Tau+AC-4-130 groups. Arrows indicate hCD45+ and/or Ferritin+ staining. Scale bar: 20 μm. Representative images of IBA+/hN+ human microglia in DS-A455D-DSAD-Tau+vehicle and DS-A455D-DSAD-Tau+AC-4-130 groups. Scale bars: 5 μm b, Quantification of microglia volumes (Data represent both sexes combined, n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, **P = 0.0079. Data are presented as mean ± SEM. c, Quantification of the process length, soma size, and soma size/process length (n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0317, **P = 0.0079, NS, not significant. Data are presented as mean ± SEM. d, Quantification of the percentage of Ferritin in hCD45+ microglia cells (Data represent both sexes combined, n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, * P = 0.0079. Data are presented as mean ± SEM. e, Representative raw fluorescence super-resolution and 3D surface rendered images showing images of colocalization of LAMP1+ and LC3B+ in hCD45+ microglia in 4-month-old DS-A455D chimeric mice. Scale bars: 5 μm and 2 μm in the original and enlarged images, respectively. f, Quantification of LAMP1+ puncta in hCD45+ microglia in 4-month-old DS-A455D chimeric mice (Data represent both sexes combined, n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, ## P = 0.0022. Data are presented as mean ± SEM. g, Quantification of LC3B+puncta in hCD45+ microglia in 4-month-old DS-A455D chimeric mice (n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, ## P = 0.0022. Data are presented as mean ± SEM. h, Quantification of LAMP1+ and LC3B+ colocalization in hCD45+ microglia in 4-month-old DS-A455D chimeric mice (Data represent both sexes combined, n = 5 mice per group). Data were analyzed by a two-tailed unpaired t-test, ## P = 0.0022. Data are presented as mean ± SEM. i, Representative image of LTP recording slice from transverse sagittal brain sections showing the distribution of transplanted microglia in 4-month-old chimeric mouse brains. Scale bar: 300 μm.

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Extended Data Fig. 7 CSF2RB A455D mutation resilience is independent of trisomy 21.

a, Quantification of CD235+, CD43+, and Ki67+ PMPs derived from the control-WT and control-A455D hiPSC lines (n = 4, each experiment was repeated four times). Student’s t-test, NS, not significant. Data are presented as mean ± SEM. b, The A455D rate in control-WT and control-A455D PMP (n = 3, each experiment was repeated three times). Data were analyzed by a two-tailed unpaired t-test, ****P < 0.0001. Data are presented as mean ± SEM. c, Linear regression and Spearman’s correlation test of RNA-seq data between control-WT and control-A455D PMP at the full transcriptome level. d, Volcano plots comparing control-WT and control-A455D PMP. e, Flow cytometry analysis of p-STAT5 level in control-WT and control-A455D PMP. f, Quantification of p-STAT5 level in control-WT and control-A455D PMP (n = 5, each experiment was repeated five times; Geo mean: Geometric mean). Data were analyzed by a two-tailed unpaired t-test, ##P = 0.0079. Data are presented as mean ± SEM. g, Quantification of IBA-1+ and CD45+ microglia derived from the control-WT and control-A455D hiPSC lines (n = 4, each experiment was repeated four times). Data were analyzed by a two-tailed unpaired t-test, NS, not significant. Data are presented as mean ± SEM. h, Flow cytometry analysis of p-STAT5 level in control-WT and control-A455D microglia. i, Quantification of p-STAT5 expression in control-WT and control-A455D microglia (n = 5, each experiment was repeated five times; Geo mean: Geometric mean). Data were analyzed by a two-tailed unpaired t-test, ##P = 0.0079. Data are presented as mean ± SEM. j, Quantitative analysis of cell viability after Tau treatment (n = 6, each experiment was repeated six times). Data were analyzed by a one-way ANOVA followed by a Tukey multiple comparison test, *P = 0.0358 and 0.0020, ****P < 0.0001. Data are presented as mean ± SEM. k, Representative live-cell imaging of microglia from control-WT and control-A455D iPSCs in the phagocytosis of zymosan particles. Bright-field images are overlaid for reference. Scale bars: 100 μm. l, Quantification of the proportion of microglia with zymosan particles (n = 5, each experiment was repeated five times). Data were analyzed by a two-tailed unpaired t-test, ##P = 0.0079. Data are presented as mean ± SEM. m, Representative images of hTMEM119+hN+ and Ki67+hN+ in control-WT and control-A455D chimeric mice. Scale bar: 20 μm. n, Quantification of the percentage of hTMEM119 in hN+ cells from control-WT and control-A455D chimeric mice (n = 4 mice per group), Student’s t-test, NS, not significant. Data are presented as mean ± SEM. o, Quantification of the percentage of Ki67 in hN+ cells from control-WT and control-A455D chimeric mice (Data represent both sexes combined, n = 4 mice per group), Data were analyzed by a two-tailed unpaired t-test, NS, not significant. Data are presented as mean ± SEM. p, Flow cytometry analysis of p-STAT5 level in control-WT and control-A455D microglia. q, Quantification of p-STAT5 expression in control-WT and control-A455D microglia (Data represent both sexes combined, n = 4 mice per group; Geo mean: Geometric mean). Data were analyzed by a two-tailed unpaired t-test, #P = 0.0286. Data are presented as mean ± SEM. r, Representative images of Ki67+ hN+ in control-WT-DSAD-Tau and control-A455D DSAD-Tau chimeric mice. Scale bars: 20 μm and 10 μm in the original and enlarged images, respectively. s, Quantification of the percentage of Ki67+ in hN+ cells from control-WT-DSAD-Tau and control-A455D DSAD-Tau chimeric mice (Data represent both sexes combined, n = 5 mice per group), Data were analyzed by a two-tailed unpaired t-test, ##P = 0.0079. Data are presented as mean ± SEM.

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Extended Data Fig. 8 The influence of CSF2RB A455D mutation in Control microglia.

a, Representative images showing colocalization of hCD45+ and Ferritin+ staining in CAGG-WT-DSAD-Tau and CAGG-A455D-DSAD-Tau groups. Arrows indicate hCD45+ and/or Ferritin+ staining. Scale bar: 20 μm. Representative images of IBA+/hN+ human microglia in control-Tau and DSAD-Tau groups. Scale bars: 5 μm b, Quantification of microglia volumes in CAGG-WT and CAGG-A455D microglia following control and DSAD Tau injection (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286. Data are presented as mean ± SEM. c, Quantification of the process length, soma size, and soma size/process length (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286, NS, not significant. Data are presented as mean ± SEM. d, Quantification of the percentage of Ferritin in hCD45+ cells (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286. Data are presented as mean ± SEM. e, Representative image of LTP recording slice from transverse sagittal brain sections showing the distribution of transplanted microglia in 6-month-old chimeric mice. Scale bar: 300 μm. f, Whole transcriptomic level linear regression and Spearman’s correlation analysis of gene expression levels from bulk RNA-seq data, comparing GFP+ and GFP− WT/A455D PMPs.

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Extended Data Fig. 9 scRNA-seq analysis of control A455D microglia and control WT microglia exposed to DSAD-Tau S1 fraction.

a, Representative images from sagittal brain sections showing the distribution of transplanted CAGG-A455D and control-WT at the age of 6-month-old chimeric mice. Scale bar: 300 μm. b, Quantification of the percentage of control-WT and CAGG-A455D microglia in total microglia cells from 6-month-old chimeric mice (Data represent both sexes combined, n = 4 mice per group), Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286, NS, not significant. Data are presented as mean ± SEM. c, Representative raw fluorescence super-resolution and 3D surface rendered images showing images of colocalization of LC3B+ in hCD45+ microglia and GFP+ microglia in 6-month-old CAGG-A455D-control-WT chimeric mice receiving injection of DSAD Tau at the age of 8 weeks. Scale bars: 5 μm and 2 μm in the original and enlarged images, respectively. d, Quantification of LC3B+ puncta in control-WT and CAGG-A455D microglia following DSAD-Tau injection (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286. Data are presented as mean ± SEM. e, Representative raw fluorescence super-resolution and 3D surface rendered images showing images of colocalization of CD68+ in hTMEM119+ microglia and GFP+ microglia in 6-month-old CAGG-A455D-control-WT chimeric mice receiving injection of DSAD Tau at the age of 8 weeks. Scale bars: 5 μm and 2 μm in the original and enlarged images, respectively. f, Quantification of CD68+ puncta in control-WT and CAGG-A455D microglia following DSAD-Tau injection (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286. Data are presented as mean ± SEM. g, Representative images of Dcx and NeuN staining in 6-month-old chimeric mice. Scale bars: 20 μm. h, Quantification of Dcx+ cells (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, NS, not significant. Data are presented as mean ± SEM. i, Scatter plot showing significantly (adj. p-value < 0.05) differentially expressed genes between two comparison groups ranked by average logFC. Genes located in the third quadrant are those both downregulated in DS-A455D-DSAD-tau compared to DS-control-DSAD-tau and downregulated in WT-A455D-DSAD-tau relative to WT-control-DSAD-tau. j-k, Reactome and GO-BP enrichment analyses of the co-downregulated genes. l, Violin plots showing the senescence score of co-transplantation each group. Wilcoxon test, n.s.: not significant, ***P < 0.001.

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Extended Data Fig. 10 Control A455D microglia replace Control WT microglia in the tau pathology model.

a-b, Representative image of brain sections from animals (6 months or 10 months of age) expressing P301L-Tau. Scale bar, 500 μm and 20 μm respectively. c-e, Representative images of panel antibodies targeting tau forms, including total transgenic tau (HT7), phosphor-tau (AT8 and PHF1) in the hippocampus of chimeric mice brains (6 months of age) expressing P301L-Tau. Scale bar, 20 μm. f, Representative images showing colocalization of hTMEM119+ microglia and P301L-Tau in 6-month-old chimeric mice. Scale bar: 50 μm. g, Representative images showing colocalization of hCD45+ GFP+ and hCD45+ GFP− staining in 6-month-old chimeric mice. Scale bar: 20 μm. h, Quantification of the percentage of CAGG-WT (hCD45+ GFP+) and Control-A455D (hCD45+ GFP−) microglia in total hCD45+ microglia cells from 6-month-old chimeric mice (Data represent both sexes combined, n = 4 mice per group), Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286, NS, not significant. Data are presented as mean ± SEM. i, Representative raw fluorescence super-resolution and 3D surface rendered images showing images of hCD45+GFP+ microglia and hCD45+GFP− microglia in 6-month-old chimeric mice receiving injection of AAV-P301L-Tau. Scale bars: 5 μm and 2 μm in the original and enlarged images, respectively. j-l, Quantification of the process length, soma size, and soma size/process length (Data represent both sexes combined, n = 4 mice per group). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286. Data are presented as mean ± SEM. m, Quantification of the microglia volumes of CAGG-WT and Control-A455D in the AAV-P301L-Tau group (Data represent both sexes combined, n = 4 mice). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286. Data are presented as mean ± SEM. n, Representative raw fluorescence super-resolution and 3D surface rendered images showing colocalization of hCD45+ GFP− microglia and GFP+ staining in 6-month-old chimeric mice receiving injection of AAV-P301L-Tau at the age of 8 weeks. Scale bar: 5 μm, 3 μm, and 2μm in the original and enlarged images, respectively. o, Quantification of the GFP volumes of CAGG-WT and control-A455D in the AAV-P301L-Tau group (Data represent both sexes combined, n = 4 mice). Data were analyzed by a two-tailed unpaired t-test, *P = 0.0286. Data are presented as mean ± SEM.

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Jin, M., Ma, Z., Dang, R. et al. A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease. Nat Neurosci 29, 25–39 (2026). https://doi.org/10.1038/s41593-025-02117-8

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