Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease
Ethan R. Roy, … , Hui Zheng, Wei Cao
Ethan R. Roy, … , Hui Zheng, Wei Cao
Published January 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1912-1930. https://doi.org/10.1172/JCI133737.
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Research Article Immunology Neuroscience

Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease

Abstract

Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we demonstrated a potent IFN immunogenicity of nucleic acid–containing (NA-containing) amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected in the brains of multiple murine Alzheimer disease (AD) models, a phenomenon also observed in WT mouse brain challenged with generic NA-containing amyloid fibrils. In vitro, microglia innately responded to NA-containing amyloid fibrils. In AD models, activated ISG-expressing microglia exclusively surrounded NA+ amyloid β plaques, which accumulated in an age-dependent manner. Brain administration of rIFN-β resulted in microglial activation and complement C3-dependent synapse elimination in vivo. Conversely, selective IFN receptor blockade effectively diminished the ongoing microgliosis and synapse loss in AD models. Moreover, we detected activated ISG-expressing microglia enveloping NA-containing neuritic plaques in postmortem brains of patients with AD. Gene expression interrogation revealed that IFN pathway was grossly upregulated in clinical AD and significantly correlated with disease severity and complement activation. Therefore, IFN constitutes a pivotal element within the neuroinflammatory network of AD and critically contributes to neuropathogenic processes.

Authors

Ethan R. Roy, Baiping Wang, Ying-wooi Wan, Gabriel Chiu, Allysa Cole, Zhuoran Yin, Nicholas E. Propson, Yin Xu, Joanna L. Jankowsky, Zhandong Liu, Virginia M.-Y. Lee, John Q. Trojanowski, Stephen D. Ginsberg, Oleg Butovsky, Hui Zheng, Wei Cao

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Figure 10

IFN pathway activation is manifested in human AD.

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IFN pathway activation is manifested in human AD. (A) Examination of IBA...
(A) Examination of IBA1+ microglia surrounding neuritic plaques in human AD specimens (n = 3). Plaques were stained with Aβ (6E10) and nucleic acids with acridine orange (AO). Correlation analysis was performed with the total cell volume of recruited microglia and the level of AO+ signal inside plaques (n = 54 plaques from 3 AD cases; r = 0.68, P < 0.0001). Scale bar: 10 μm. Additional representative images are shown in Supplemental Figure 25. (B) Representative confocal images of neuritic plaque-associated microglia in human AD cases (n = 3) expressing ISGs: IFITM3 (left) and AXL (right). Insets show single-channel images of outlined areas. Scale bar: 10 μm. Signals in microglia from plaque-free areas are shown in Supplemental Figure 27. (C and D) Heatmaps showing group-averaged expression of human ISGs in postmortem brain tissue (parahippocampal gyrus) from 175 human subjects stratified by clinical dementia rating (CDR) (C) and Braak score (D). NCI indicates no cognitive impairment; MCI, mild cognitive impairment. Individual ISGs with differential expression are highlighted. See also Supplemental Figure 28 for other brain regions. (E and F) Correlations of IRF7 transcript level with CDR, Braak score (E), and mean neuritic plaque density (F). (G) Correlation of IRF7 transcript level with C3 transcript level. (H) Coexpression analysis between IFN pathway genes (yellow) and complement genes (green). Links inside the circle represent significant (P < 0.8 × 10–5) Spearman correlation coefficients between the genes (gray: r > 0.6; blue: r < 0.6). Coexpression analysis between IFN pathway genes and random gene sets is shown in Supplemental Figure 30 as a control. For A, E, F, and G, correlation coefficients (r) were computed using Pearson correlations (A, F, G) or Spearman correlations (E). All: P <0.0001. For A, F, and G, plots display one dot for each plaque (A) or subject (F, G), and linear regression line (solid) with 95% CI (dashed).