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Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology
Open accessAbstract
The impact of inflammation suppressor pathways on Alzheimer's disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1(+)Il10(-/-)). Quantitative in silico 3D modeling revealed activated Aβ phagocytic microglia in APP/PS1(+)Il10(-/-) mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1(+)Il10(-/-) brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβ uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that "rebalancing" innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.
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“CCL20 (55), CSF3 (56) and IL10 (57) are associated with the inflammatory response in AD.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [57]
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“Il10 deletion led to increased Aβ phagocytosis and increased CD68 reactivity in Aβ depositassociated microglia (133).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [133]
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“an independent study documented a role for the IL10-STAT3 pathway in mediating microglial Aβ phagocytosis (Guillot-Sestier et al., 2015).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Guillot-Sestier et al., 2015
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“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 [121]
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Metadata
- Authors
- Guillot-Sestier, M.-V., Doty, K. R., Gate, D., Rodriguez, J., Leung, B. P., Rezai-Zadeh, K., & Town, T.
- Affiliations
- University of Southern California (US)
- Pennington Biomedical Research Center (US)
- Corresponding author
- Town, Terrence
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 85
- Issue
- 3
- Pages
- 534-548
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4352138
- OpenAlex
- W1999516517
- Cited by
- 363
- References
- 79
- Citations by year
- 2026: 19 · 2025: 18 · 2024: 30 · 2023: 26 · 2022: 33 · 2021: 34 · 2020: 39 · 2019: 33 · 2018: 28 · 2017: 41 · 2016: 43 · 2015: 19
- FWCI
- 23.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1f31ns083339-01a1)
- National Institute on Aging (R00AG029726)
- National Institute of Neurological Disorders and Stroke (1F31NS083339-01A1, R01NS076794)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- IL-10, Alzheimer's disease, APP/PS1 mice, cerebral amyloidosis, microglia, amyloid-beta phagocytosis, innate immunity, neuroinflammation, STAT3 signaling, apolipoprotein E, synaptic integrity, cognitive impairment, anti-inflammatory cytokines
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Female, Humans, Immunity, Innate, Male, Mice, Inbred C57BL, Mice, Transgenic, Interleukin-10, Mice, Knockout, Mice
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