Concerted Type I Interferon Signaling in Microglia and Neural Cells Promotes Memory Impairment Associated With Amyloid β Plaques

Authors

Ethan R Roy
Gabriel Chiu
Sanming Li
Nicholas E Propson
Rupa Kanchi
Baiping Wang
Cristian Coarfa
Hui Zheng
Wei Cao

Publication Date

5-10-2022

Journal

Immunity

DOI

10.1016/j.immuni.2022.03.018

PMID

35443157

PMCID

PMC9109419

PubMedCentral® Posted Date

5-10-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Disease Models, Animal, Immunity, Innate, Interferon Type I, Memory Disorders, Mice, Mice, Transgenic, Microglia, Plaque, Amyloid, interferon, memory impairment, neuroinflammation, synapse, microglia, Alzheimer’s disease

Abstract

The principal signals that drive memory and cognitive impairment in Alzheimer's disease (AD) remain elusive. Here, we revealed brain-wide cellular reactions to type I interferon (IFN-I), an innate immune cytokine aberrantly elicited by amyloid β plaques, and examined their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Using a fate-mapping reporter system to track cellular responses to IFN-I, we detected robust, Aβ-pathology-dependent IFN-I activation in microglia and other cell types. Long-term blockade of IFN-I receptor (IFNAR) rescued both memory and synaptic deficits and resulted in reduced microgliosis, inflammation, and neuritic pathology. Microglia-specific Ifnar1 deletion attenuated the loss of post-synaptic terminals by selective engulfment, whereas neural Ifnar1 deletion restored pre-synaptic terminals and decreased plaque accumulation. Overall, IFN-I signaling represents a critical module within the neuroinflammatory network of AD and prompts concerted cellular states that are detrimental to memory and cognition.

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