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

Paramita Chakrabarty, Andrew Li, Carolina Ceballos-Diaz, James A. Eddy, Cory C. Funk, Brenda Moore, Nadia Di Nunno, Awilda M. Rosario, Pedro E. Cruz, Christophe Verbeeck, Amanda Sacino, Sarah Nix, Christopher Janus, Nathan D. Price, Pritam Das, Todd E. Golde

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Abstract

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. Exvivo 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.

Original languageEnglish (US)
Pages (from-to)519-533
Number of pages15
JournalNeuron
Volume85
Issue number3
DOIs
StatePublished - Feb 4 2015

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Interleukin-10
Apolipoproteins E
Anti-Inflammatory Agents
Dependovirus
Gene Expression Profiling
Phagocytosis
Innate Immunity
Neuroglia
Neurodegenerative Diseases
Cognition
Transgenic Mice
Alzheimer Disease
Pathology
Cytokines
Brain
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., ... Golde, T. E. (2015). IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior. Neuron, 85(3), 519-533. https://doi.org/10.1016/j.neuron.2014.11.020

IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior. / Chakrabarty, Paramita; Li, Andrew; Ceballos-Diaz, Carolina; Eddy, James A.; Funk, Cory C.; Moore, Brenda; Di Nunno, Nadia; Rosario, Awilda M.; Cruz, Pedro E.; Verbeeck, Christophe; Sacino, Amanda; Nix, Sarah; Janus, Christopher; Price, Nathan D.; Das, Pritam; Golde, Todd E.

In: Neuron, Vol. 85, No. 3, 04.02.2015, p. 519-533.

Research output: Contribution to journalArticle

Chakrabarty, P, Li, A, Ceballos-Diaz, C, Eddy, JA, Funk, CC, Moore, B, Di Nunno, N, Rosario, AM, Cruz, PE, Verbeeck, C, Sacino, A, Nix, S, Janus, C, Price, ND, Das, P & Golde, TE 2015, 'IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior', Neuron, vol. 85, no. 3, pp. 519-533. https://doi.org/10.1016/j.neuron.2014.11.020
Chakrabarty, Paramita ; Li, Andrew ; Ceballos-Diaz, Carolina ; Eddy, James A. ; Funk, Cory C. ; Moore, Brenda ; Di Nunno, Nadia ; Rosario, Awilda M. ; Cruz, Pedro E. ; Verbeeck, Christophe ; Sacino, Amanda ; Nix, Sarah ; Janus, Christopher ; Price, Nathan D. ; Das, Pritam ; Golde, Todd E. / IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior. In: Neuron. 2015 ; Vol. 85, No. 3. pp. 519-533.
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