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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

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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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