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

doi:10.1016/j.neuron.2014.11.020

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

Research output: Contribution to journal › Article › peer-review

214 Scopus citations

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 language	English (US)
Pages (from-to)	519-533
Number of pages	15
Journal	Neuron
Volume	85
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2014.11.020
State	Published - Feb 4 2015
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2014.11.020

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Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., Di Nunno, N., Rosario, A. M., Cruz, P. E., Verbeeck, C., Sacino, A., Nix, S., Janus, C., Price, N. D., Das, P., & 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

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

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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.",

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

note = "Funding Information: This work was supported by NIH grants RO1AG32991 (P.D.) and R01AG018454 (T.E.G.) and NIA grant AG046139-01 (T.E.G., N.P.). We thank Drs. Terrence Town and Marie-Victoire Guillot-Sestier (University of Southern California) for helpful discussion. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

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AU - Chakrabarty, Paramita

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AU - Eddy, James A.

AU - Funk, Cory C.

AU - Moore, Brenda

AU - Di Nunno, Nadia

AU - Rosario, Awilda M.

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AU - Verbeeck, Christophe

AU - Sacino, Amanda

AU - Nix, Sarah

AU - Janus, Christopher

AU - Price, Nathan D.

AU - Das, Pritam

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N2 - 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.

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

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