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[220520 저널발표] Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid-beta plaques

정선우 │ 2022-05-17

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Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid-β plaques

Immunity. 2022. May 10;55(5):879-894.e6.

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.

Keywords: Alzheimer’s disease; interferon; memory impairment; microglia; neuroinflammation; synapse.





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