Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease
Autor: | Hui Zheng, Oleg Butovsky, Gabriel Chiu, Allysa L. Cole, Virginia M.-Y. Lee, Zhuoran Yin, Baiping Wang, Wei Cao, Ying-Wooi Wan, Stephen D. Ginsberg, Nicholas E. Propson, Joanna L. Jankowsky, Zhandong Liu, Yin Xu, John Q. Trojanowski, Ethan R. Roy |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Amyloid Biology Microgliosis Antiviral Agents Article Synapse 03 medical and health sciences Mice 0302 clinical medicine Interferon Alzheimer Disease medicine Animals Humans Senile plaques Neuroinflammation Inflammation Amyloid beta-Peptides Microglia Brain General Medicine Complement C3 Interferon-beta medicine.disease Complement system Up-Regulation Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Interferon Type I Synapses Alzheimer's disease medicine.drug Research Article |
Zdroj: | J Clin Invest J Alzheimers Dis |
Popis: | 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. |
Databáze: | OpenAIRE |
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