Neuron
Volume 85, Issue 3, 4 February 2015, Pages 519-533
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Article
IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior

https://doi.org/10.1016/j.neuron.2014.11.020Get rights and content
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Highlights

  • The anti-inflammatory cytokine, IL-10, increases Aβ accumulation in APP mouse brain

  • IL-10 exacerbates memory impairment in APP mice and reduces synaptic proteins

  • IL-10 increases ApoE, which, by binding aggregated Aβ, is sequestered in plaques

  • IL-10 and ApoE suppress microglial Aβ phagocytosis in vitro

Summary

Anti-inflammatory strategies are proposed to have beneficial effects in Alzheimer’s disease. To explore how anti-inflammatory cytokine signaling affects Aβ pathology, we investigated the effects of adeno-associated virus (AAV2/1)-mediated expression of Interleukin (IL)-10 in the brains of APP transgenic mouse models. IL-10 expression resulted in increased Aβ accumulation and impaired memory in APP mice. A focused transcriptome analysis revealed changes consistent with enhanced IL-10 signaling and increased ApoE expression in IL-10-expressing APP mice. ApoE protein was selectively increased in the plaque-associated insoluble cellular fraction, likely because of direct interaction with aggregated Aβ in the IL-10-expressing APP mice. Ex vivo studies also show that IL-10 and ApoE can individually impair glial Aβ phagocytosis. Our observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and proteostasis in neurodegenerative diseases, an interaction we call immunoproteostasis.

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Present address: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA