Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 4, Pages 1912-1930Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI133737
Keywords
-
Categories
Funding
- NIH [AG057587, AG032051, AG020670, AG054111, NS092515, AG051812, AG054672]
- Robert A. and Rene E. Belfer Family Foundation
- BrightFocus ADR [A20183775]
- Cure Alzheimer's Fund
- TBMM T32 training grant [ST32GM088129]
Ask authors/readers for more resources
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 beta-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 beta plaques, which accumulated in an age-dependent manner. Brain administration of rIFN-beta 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available