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Concerted cellular responses to type I interferon propel memory impairment associated with amyloid β plaques

By Ethan R Roy, Gabriel Chiu, Sanming Li, Nicholas E. Propson, Hui Zheng, Wei Cao

Posted 03 Nov 2021
bioRxiv DOI: 10.1101/2021.11.01.466525

Despite well-documented maladaptive neuroinflammation in Alzheimer's disease (AD), the principal signal that drives memory and cognitive impairment remains elusive. Here, we reveal robust, age-dependent cellular reactions to type I interferon (IFN), an innate immune cytokine aberrantly elicited by beta-amyloid plaques, and examine their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Long-term blockade of IFN receptor rescued both memory and synaptic deficits and resulted in reduced microgliosis, inflammation, and neuritic pathology. Interestingly, microglia-specific IFN receptor ablation attenuated the loss of post-synaptic terminals, whereas IFN signaling in neural cells contributed to pre-synaptic alteration and plaque accumulation. Intriguingly, IFN pathway activation displayed a strong inverse correlation with cognitive performance, promoting selective synapse engulfment by microglia rather than amyloid plaques. Overall, IFN signaling represents a critical module within the neuroinflammatory network of AD and prompts a concerted cellular state that is detrimental to memory and cognition.

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