IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior

• Published in: Neuron (Cambridge, Mass.) Vol. 85; no. 3; pp. 519 - 533
• Main Authors: Chakrabarty, Paramita, Li, Andrew, Ceballos-Diaz, Carolina, Eddy, James A., Funk, Cory C., Moore, Brenda, DiNunno, Nadia, Rosario, Awilda M., Cruz, Pedro E., Verbeeck, Christophe, Sacino, Amanda, Nix, Sarah, Janus, Christopher, Price, Nathan D., Das, Pritam, Golde, Todd E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.02.2015; Elsevier Limited
• Subjects: Adeno-associated virus; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Animal cognition; Animals; Animals, Newborn; Cells, Cultured; Cognition Disorders - immunology; Cognition Disorders - metabolism; HEK293 Cells; Humans; Hypotheses; Immune system; Immunoproteins - biosynthesis; Interleukin-10 - biosynthesis; Memory; Mice; Mice, Transgenic; Neurodegeneration; Plaque, Amyloid - immunology; Plaque, Amyloid - metabolism; Proteostasis Deficiencies - immunology; Proteostasis Deficiencies - metabolism; Rodents
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2014.11.020

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. •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 Chakrabarty et al. show that Interleukin-10 increases Aβ plaque deposition and impairs cognition in APP mice. This is mechanistically linked to decreased microglial Aβ phagocytosis and increased ApoE expression and sequestration in plaques, consistent with ApoE’s role as a pathological chaperone.