Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology

Shaftel, Solomon S.; Kyrkanides, Stephanos; Olschowka, John A.; Miller, Jen-nie H.; Johnson, Renee E.; O’Banion, M. Kerry

doi:10.1172/jci31450

Cited by 433Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology

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Shaftel, Solomon S., Kyrkanides, Stephanos, Olschowka, John A., Miller, Jen-nie H., Johnson, Renee E., O’Banion, M. Kerry·2007·Journal of Clinical Investigation

DOI 10.1172/jci31450PMC PMC1878531

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Abstract

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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IL1β overexpression enhances Aβ clearance.
“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]
The section “IL-1β overexpression reduces amyloid pathology” (page unavailable) reports reduced plaques and insoluble Aβ40 and Aβ42 in APP/PS1 mice after IL-1β overexpression. The Discussion describes plaque clearance and degradation as proposed explanations, but does not demonstrate increased Aβ clearance directly; “demonstrated” overstates that mechanistic finding. (LLM, conf=0.84)
Experimental — accuracy not yet measured
IL-1β does not influence Aβ production.
“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]
In “IL-1β overexpression reduces amyloid pathology” (page not supplied), the paper reports no evidence that IL-1β altered APP or BACE-1 expression or activity, and concludes that reduced plaques in its mouse model were likely not due to changes in Aβ synthesis. That supports the claim for this model, but not the unqualified assertion that IL-1β does not influence Aβ production generally. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Activated micro/astroglia enhances Aβ phagocytosis.
“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]
The Discussion says activated microglia overlapped more with plaques and that this could potentially increase plaque phagocytosis; it does not demonstrate increased phagocytosis. The neuroinflammatory-phenotype section reports astrocyte activation but does not link astrocytes to Aβ phagocytosis. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Overexpression of IL1β, an inflammatory cytokine, leads to reduced Aβ pathology in mouse models of AD.
“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]
Various genetically modified mouse models have demonstrated a role for other chemokines/cytokine pathways, including CCR2 and IL1β, in altering the accumulation of mononuclear phagocytes and Aβ pathology.
“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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“Interestingly, other evidence demonstrates that triggering localized hippocampal IL-1 overexpression mediates a substantial reduction in plaque pathology through microglial cell activation suggesting a dual effect of IL-1 in mediating inflammation in AD [42].”
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A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants
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CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model
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In Brief
(2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2391
Chronic IL-1β-Mediated Neuroinflammation Mitigates Amyloid Pathology in a Mouse Model of Alzheimer’s Disease without Inducing Overt Neurodegeneration
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Self-citation
P4‐178: Sustained Interleukin‐1 expression drives plaque clearance in a mouse model of Alzheimer's disease
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Self-citation
Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an alzheimer’s mouse model
Ghosh, S., Wu, M. D., Shaftel, S. S., Kyrkanides, S., LaFerla, F. M., Olschowka, J. A., & O'Banion, M. K. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4361-12.2013 · Cited by 390 · see citing works
Self-citation
A beneficial role for IL-1β in Alzheimer disease?
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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
ORCID: Kyrkanides, Stephanos
Olschowka, John A.
O’Banion, M. Kerry
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2007-06-01
Volume: 117
Issue: 6
Pages: 1595-1604
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci31450
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
Health Sciences › Medicine › Physiology › 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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Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology

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