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Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology
Open accessAbstract
Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1 beta has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1 beta overexpression that was capable of driving robust neuroinflammation lasting months after transgene activation. This response was characterized by astrocytic and microglial activation in addition to induction of proinflammatory cytokines. Surprisingly, when triggered in the hippocampus of the APPswe/PS1dE9 mouse model of AD, 4 weeks of IL-1 beta overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (A beta 40) and A beta 42 decreased significantly. These results demonstrate a possible adaptive role for IL-1 beta-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.
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“previous studies demonstrated that IL1 overexpression enhances A clearance.9,53”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“This is consistent with our previously published data showing that IL-1β does not influence Aβ production [4, 6, 7, 28].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“For amyloid pathology, there is data that activated micro/astroglia enhances Aβ phagocytosis [60, 62, 71]”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [62]
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“Recent studies demonstrated that overexpression of IL1, an inflammatory cytokine leads to reduced A pathology in mouse models of AD. 9,53”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [9]
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“Various genetically modified mouse models have convincingly demonstrated the role for other chemokines/cytokine pathways in altering the accumulation of mononuclear phagocytes (monocytes, macrophages, and microglia) and A pathology, including CCR2 59 and IL1.9”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [9]
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“numerous other studies have suggested that altering the proliferation, 58 signaling, 8,9,11 and migration 7,59 of microglia directly impact development of A pathology.”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [9]
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“As previously described [28], APP/PS1 mice transduced with rAAV2-IL-1β showed significant reductions in hippocampal amyloid plaques compared to mice treated with rAAV2-Phe, as determined by immunohistochemical (IHC) analysis using both 6E10 staining and MX04 (Fig. 1b)”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [4]
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“Hippocampal expression of IL-1β was shown to robustly reduce plaques in the APP/PS1 model and 3xTg-AD model but worsened tauopathy in the 3xTg-AD model [62, 63].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [62]
In the citing paper
“In turn, increased cytokines, such as interleukin-1, can influence Aβ uptake (Mrak and Griffin, 2000; Shaftel et al., 2007).”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Shaftel et al., 2007
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Metadata
- Authors
- Shaftel, S. S., Kyrkanides, S., Olschowka, J. A., Miller, J.-N. H., Johnson, R. E., & O’Banion, M. K.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- O’Banion, M. Kerry
- Venue
- Journal of Clinical Investigation
- Published
- 2007-06-01
- Volume
- 117
- Issue
- 6
- Pages
- 1595-1604
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1878531
- OpenAlex
- W2105385589
- Cited by
- 433
- References
- 46
- Citations by year
- 2026: 8 · 2025: 25 · 2024: 16 · 2023: 18 · 2022: 34 · 2021: 22 · 2020: 20 · 2019: 26 · 2018: 23 · 2017: 20 · 2016: 18 · 2015: 24 · 2014: 32 · 2013: 26 · 2012: 35
- FWCI
- 12.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Rochester
- National Institutes of Health (14642)
- Medical Center, University of Rochester
- National Institute of General Medical Sciences (GM 07356, T32GM007356)
- National Institute of Neurological Disorders and Stroke (NS048522, R29NS033553, NS 33553, R21NS048522, R01NS033553)
- 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-1β, neuroinflammation, Alzheimer's disease, amyloid plaques, hippocampus, astrocyte activation, microglial activation, inflammatory cytokines, APPswe/PS1dE9 transgenic mice, amyloid-beta
- MeSH terms
- Alzheimer Disease, Animals, Base Sequence, Disease Models, Animal, Hippocampus, Humans, Inflammation, Mice, Transgenic, Nerve Degeneration, Recombinant Proteins, Gene Expression, Amyloid beta-Protein Precursor, DNA Primers, Mice, Interleukin-1beta, Presenilin-1, Plaque, Amyloid
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