IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior
Open accessAbstract
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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Microglial cells play pivotal role in maintaining immunoproteostasis through phagocytosis and degradation of misfolded proteins, their protective function is inseparably associated with immune activation exerting a chronic, potentially harmful effect on the regional milieu of neuronal networks.
“Though microglial cells play pivotal role in maintaining immunoproteostasis through phagocytosis and degradation of misfolded proteins, their protective function is inseparably associated with immune activation exerting a chronic, potentially harmful effect on the regional milieu of neuronal networks [35, 37–39].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [35]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredExcessive apoE accumulation within Aβ plaques impairs ability of microglia to contain plaque load.
“which can be tied to a recent discovery showing that excessive apoE accumulation within Aβ plaques impairs ability of microglia to contain plaque load [35].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [35]
The Results (Figure 8) report increased ApoE within Aβ plaques in IL-10/Tg mice and reduced fluorescent Aβ uptake by microglia exposed to ApoE-conditioned media. The Discussion proposes that ApoE bound to Aβ aggregates may hinder clearance and promote plaque deposition. It does not directly establish that ApoE accumulated within plaques impairs microglia’s ability to contain plaque load, as the citing sentence states. (LLM, conf=0.85)
Experimental — accuracy not yet measuredApoE binds amyloid β and attenuates the uptake of amyloid β by cultured microglia.
“The same group also reported that ApoE binds amyloid β and attenuates the uptake of amyloid β by cultured microglia [36].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [36]
IL-10 levels are elevated in Alzheimer's disease brain, and IL-10 overexpression in mice increases APOE expression and worsens AD-related pathology and cognitive impairment.
“IL-10 levels are elevated in AD brain, and IL-10 overexpression in mice increased APOE expression in addition to worsening AD-related pathology and cognitive impairment (132).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [132]
Data examining the effects of microglia and inflammatory mediators on Aβ deposition in APP transgenic mice are mixed, with some studies showing reduced and others exacerbated Aβ accumulation.
“Similarly, data examining the effects of microglia and inflammatory mediators on Aβ deposition in APP transgenic mice are mixed, with some studies demonstrating reduced and others exacerbated Aβ accumulation [120–122].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [120]
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References 77 · Cited by 354
- Authors
- Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., DiNunno, N., Rosario, A. M., Cruz, P. E., Verbeeck, C., Sacino, A., Nix, S., Janus, C., Price, N. D., Das, P., & Golde, T. E.
- Affiliations
- University of Florida (US)
- Institute for Systems Biology (US)
- Mayo Clinic (US)
- Corresponding author
- Chakrabarty, Paramita
- Golde, Todd E.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 85
- Issue
- 3
- Pages
- 519-533
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4320003
- OpenAlex
- W2096401612
- Cited by
- 354
- References
- 77
- Citations by year
- 2026: 15 · 2025: 16 · 2024: 22 · 2023: 13 · 2022: 30 · 2021: 33 · 2020: 46 · 2019: 32 · 2018: 33 · 2017: 47 · 2016: 40 · 2015: 27
- FWCI
- 35.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG046139‐01, R01AG032991, R01AG018454, U01AG046139)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- IL-10, Alzheimer's disease, amyloid-beta, amyloid plaques, APP transgenic mice, anti-inflammatory cytokines, apolipoprotein E, memory impairment, glial phagocytosis, innate immunity, proteostasis, gene expression profiling
- MeSH terms
- Animals, Animals, Newborn, Cells, Cultured, Cognition Disorders, Humans, Immunoproteins, Mice, Transgenic, Amyloid beta-Protein Precursor, Interleukin-10, Mice, Proteostasis Deficiencies, HEK293 Cells, Plaque, Amyloid
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