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Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice

Nature Aging volume 3, pages 202–212 (2023)Cite this article

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Abstract

cGAS senses microbial and host-derived double-stranded DNA in cytoplasm to trigger cellular innate immune response in a STING-dependent manner; however, it remains unknown whether the cGAS-STING pathway in innate immunity contributes to Alzheimer’s disease (AD). Here we demonstrated the detectable binding of the cGAS double-stranded DNA in cytoplasm and the activation of the microglial cGAS-STING pathway in brains of human AD and aged mice. Cgas−/−;5×FAD mice were largely protected from cognitive impairment, amyloid-β pathology, neuroinflammation and other sequelae associated with AD. Furthermore, Cgas deficiency in microglia inhibited a neurotoxic A1 astrocytic phenotype and thus alleviated oligomeric amyloid-β peptide-induced neurotoxicity. Finally, administration of STING inhibitor H-151 potently suppressed the activation of the cGAS-STING pathway and ameliorated AD pathogenesis in 5×FAD mice. In conclusion, our present study has identified a critical molecular link between innate immunity and AD and suggests that therapeutic targeting of the cGAS-STING pathway activity might effectively interfere with the progression of AD.

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Fig. 1: cGAS-STING pathway is activated in brains during AD and aging.
Fig. 2: cGAS deficiency alleviates cognitive decline, Aβ pathology and neuroinflammation in 5×FAD mice.
Fig. 3: The suppression of neurotoxic A1 astrocytes by cGAS deficient microglia is neuroprotective from Aβ toxicity.
Fig. 4: Administration of STING inhibitor H-151 ameliorates Aβ pathology and neuroinflammation in 5×FAD mice.

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All data necessary to understand and evaluate the conclusion of this paper are provided in the article, its Source Data and Supplementary Information. Any other data can be obtained from the corresponding author upon reasonable request.

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Acknowledgements

We thank B. Lu from the Central South University in China for providing additional Cgas−/− mice and Y.-H. He from the Kunming Institute of Zoology, Chinese Academy of Sciences for providing partial aged mice samples. The graphical diagram is produced by BioRender. This work was supported by Yunnan Fundamental Research Projects (grant no. 202201AW070020).

Author information

Author notes

  1. These authors contributed equally: Xiaochun Xie, Guanqin Ma, Xiaohong Li.

Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    Xiaochun Xie, Guanqin Ma, Xiaohong Li, Jiebin Zhao & Jianxiong Zeng

  2. Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA, USA

    Xiaochun Xie, Zhen Zhao & Jianxiong Zeng

  3. Zikha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Xiaochun Xie, Zhen Zhao & Jianxiong Zeng

  4. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China

    Jianxiong Zeng

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Contributions

All authors read and approved the final version of the manuscript. J.Z. and Z.Z. conceived the research and designed the study. J.Z. and Z.Z. wrote the manuscript. X.X., G.M., X.L. and J.B.Z. performed the experiments and discussed the data. All authors commented on the manuscript.

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Nature Aging thanks Marco Colonna, Hitoshi Okazawa, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Yahyah Aman, in collaboration with the Nature Aging team.

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Extended data

Extended Data Fig. 1 The binding partner of cGAS and cytosolic or nucleus dsDNA in the brain of human AD and aged mice.

a, Quantification of cmtDNA by qPCR in brain cells of 2-month-old 5 × FAD mice and age-matched WT mice. b, Quantification of total cellular mtDNA by qPCR in brain cells of 6-month-old 5 × FAD mice and age-matched WT mice. D-loop indicated a specific fragment within mtDNA. Mean ± SD; n = 4 or 6; n.s., not significant, two-tailed Student’s t-test. c, PLA as indicated by white arrow showing the association of cGAS protein with cytosolic or nucleus DNA in hippocampal tissues of human AD samples. Age-matched health human samples were used as control. Scale bar, 10 μm. d, Quantification of PLA red dots per cell in c. Three sections in each animal were used to count the dots. Mean ± SD; n = 3, three sections of each brain sample were stained and counted; ***, p < 0.001, two-tailed Student’s t-test. e, f, Quantification of cmtDNA (e) and mtDNA (f) by qPCR in brain cells of 20-month-old WT mice. 3-month-old WT mice were used as control. Mean ± SD; n.s., not significant; n = 3; *, p < 0.05, **, p < 0.01, ***, p < 0.001, two-tailed Student’s t-test. g, PLA showing the association of cGAS protein with cytosolic or nucleus DNA in hippocampal tissues of 20-month-old aged WT mice. 3-month-old young WT mice were used as control. Scale bar, 10 μm. h, Quantification of PLA red dots per cell in g. Mean ± SD; n = 3, four sections of each brain sample were stained and counted; ***, p < 0.001, two-tailed Student’s t-test. i, Western immunoblotting analysis of the expression of the indicated proteins involved in cGAS-SITNG pathway of cortical tissues in 20-month-old aged WT mice. n = 3. j, Quantification of the expression of the phosphorylated STING (p-STING), TBK1 (p-TBK1), p65 (p-p65), and IRF3 (p-IRF3) relative to β-actin in i. Mean ± SD; n = 3; *, p < 0.05, **, p < 0.01, ***, p < 0.001, two-tailed Student’s t-test.

Source data

Extended Data Fig. 2 cGAS deficiency ameliorates cognitive decline and reduces microglial activation in 5 × FAD mice.

a, b, Immunostaining (a) and quantification (b) of Aβ in DG of 2~2.5 months old Cgas+/+;5 × FAD and Cgas−/−;5 × FAD mice. Scale bar, 40 μm. Mean ± SD; n = 3; n.s., not significant, two-tailed Student’s t-test. c, Behavioral analysis of burrowing in 6-month-old Cgas+/+;5 × FAD and Cgas–/–;5 × FAD mice. Age-matched Cgas+/+ and Cgas–/– mice were used as control. Mean ± SD; n = 12; ***, p < 0.001, one-way ANOVA with Bonferroni’s post hoc test. d, e, Quantification of Aβ plaque numbers in different plaque diameter (d) and percentage of Aβ plaque area (e) in DG in Fig. 2h. Mean ± SD; n = 6; *, p < 0.05, **, p < 0.01, two-tailed Student’s t-test. f, Quantification of percentage of Iba1+ area in Fig. 2h. Mean ± SD; n = 6; **, p < 0.01, two-tailed Student’s t-test. g, Western immunoblotting analysis of the expression of synaptic PSD95 and Synaptophysin of cortical tissues in 6-month-old WT, Cgas+/+;5 × FAD, and Cgas–/–;5 × FAD mice. n = 3. h, Quantification of protein levels of PSD95 and Synaptophysin relative to β-actin in g. Mean ± SD; n = 3; *, p < 0.05, ***, p < 0.001, two-tailed Student’s t-test.

Source data

Extended Data Fig. 3 cGAS-STING pathway is differentially activated in multiple types of neural cells.

a-f, Quantification of cmtDNA (a-c) and total mtDNA (d-f) in primary cultured microglia (a, d), neurons (b, e), and astrocytes (c, f) treated with oligomeric Aβ42 (5 μM) for 24 h. g-i, ELISA analysis of 2′3′-cGAMP level in oligomeric Aβ42-treated primary microglia (g), neurons (h), and astrocytes (i). j-l, ELISA analysis of IFN-β level in the supernatants of primary microglia (j), neurons (k), and astrocytes (l) treated with oligomeric Aβ42. Mean ± SD; n = 3; n.s., not significant, *, p < 0.05, **, p < 0.01, two-tailed Student’s t-test.

Source data

Extended Data Fig. 4 Additional control experiments of primary neuronal cultures.

a–c, Cgas+/+ and Cgas–/– primary neurons that were pre-infected with AAV expressing a GFP with CaMKII promotor were treated with oligomeric Aβ42 (750 nM) for 24 h (a). Fluorescent signals (b) and percentage (c) of GFP-labeled primary neurons were recorded and calculated. Scale bar, 50 μm. d-f, Cgas+/+ primary neurons that were incubated with Cgas+/+ ACM and Cgas–/– ACM without the prior MCM treatment were treated with oligomeric Aβ42 (750 nM) for 24 h (d). Fluorescent signals (e) and percentage (f) of GFP-labeled primary neurons were recorded and calculated. Scale bar, 50 μm. g-i, Cgas+/+ primary neurons that were incubated with Cgas+/+ MCM and Cgas–/– MCM without the ACM treatment were treated with oligomeric Aβ42 (750 nM) for 24 h (g). Scale bar, 50 μm. Fluorescent signals (h) and percentage (i) of GFP-labeled primary neurons were recorded and calculated. In c, f and i, Mean ± SD, n = 4, n.s., not significant by one-way ANOVA with Bonferroni’s post hoc test.

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Extended Data Fig. 5 The purification of astrocytes from brains of mice.

a, Astrocytic cells were magnetically purified by ACSA-2 MicroBeads from brains of mice. b, c, Gating strategy (b) and purity (c) of ACSA-2+ astrocyte populations by anti-ACSA-2-PE antibody in fluorescence activated cell sorter (FACS) analysis. d, Immunofluorescence analysis of purified astrocytes in cultures using anti-GFAP antibody. Scale bar, 50 μm. Representative images as shown were from the results of five mice each group. e, Transcriptional analysis for astrocytic genes in 6-month-old Cgas+/+ (n = 5) and Cgas–/– (n = 5) mice. f, GFAP+ astrocytic staining of DG in 6-month-old Cgas+/+;5 × FAD and Cgas–/–;5 × FAD mice. Scale bar, 50 μm. g, Quantification of percentage of GFAP+ area in f. Mean ± SD; n = 6; **, p < 0.01, two-tailed Student’s t-test.

Source data

Extended Data Fig. 6 The effect of cGAS-STING inhibitors-treated microglia on primary neuronal survival.

a-c, Cgas+/+ primary neurons that were incubated with RU.521 MCM and H-151 MCM without the ACM treatment were treated with oligomeric Aβ42 (750 nM) for 24 h (a). Fluorescent signals (b) and percentage (c) of GFP-labeled primary neurons were recorded and calculated. Mean ± SD, n = 4, n.s., not significant by one-way ANOVA with Bonferroni’s post hoc test.

Source data

Extended Data Fig. 7 H-151 treatment suppressed the activation of cGAS-STING pathway and the expression of the inflammatory genes.

a, Western immunoblotting analysis of the expression of the indicated proteins involved in cGAS-SITNG pathway of cortical tissues in H-151-treated 5−month-old 5 × FAD mice. n = 3. b, Quantification of the expression of the phosphorylated TBK1 (p-TBK1), phosphorylated p65 (p-p65) and phosphorylated IRF3 (p-IRF3) relative to β-actin in a. Mean ± SD; n = 3; **, p < 0.01, ***, p < 0.001, two-tailed Student’s t-test. c-f, qRT-PCR analysis of a panel of neuroinflammatory genes in cortical tissues of H-151-treated 5 × FAD mice at 5 months old. Mean ± SD; n = 4; *, p < 0.05, **, p < 0.01, two-tailed Student’s t-test.

Source data

Extended Data Fig. 8 Additional phenotypes of the H-151 treated 5 × FAD mice.

a, Immunostaining of NeuN and Aβ of DG regions in H-151-treated 5-month-old 5 × FAD mice. Scale bar, 50 μm. b, c, Quantification of percentage of NeuN+ area (b) and NeuN+ thickness (c) as indicated by white arrow in a. Mean ± SD; n = 6; n.s., not significant, Student’s t-test. d, Immunostaining of Aβ and CD68 of DG regions in H-151-treated 5-month-old 5 × FAD mice. Scale bar, 50 μm. e, Quantification of CD68/Aβ ratio in d. Mean ± SD; n = 6; **, p < 0.01, two-tailed Student’s t-test.

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Supplementary information

Reporting Summary

Supplementary Table 1

Information on frozen or paraffin-embedded blocks of postmortem human frontal lobe or hippocampus samples, respectively. Supplementary Table 2 Primers used for analysis in this study. Supplementary Table 3 Antibodies used in this study.

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Xie, X., Ma, G., Li, X. et al. Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice. Nat Aging 3, 202–212 (2023). https://doi.org/10.1038/s43587-022-00337-2

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