Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an alzheimer’s mouse model
Open accessAbstract
Neuroinflammation is an important component of Alzheimer's disease (AD) pathogenesis and has been implicated in neurodegeneration. Interleukin-1 (IL-1), a potent inflammatory cytokine in the CNS, is chronically upregulated in human AD and believed to serve as part of a vicious inflammatory cycle that drives AD pathology. To further understand the role of IL-1β in AD pathogenesis, we used an inducible model of sustained IL-1β overexpression (IL-1β XAT ) developed in our laboratory. The triple transgenic mouse model of AD, which develops plaques and tangles later in its life cycle, was bred with IL-1β XAT mice, and effects of IL-1β overexpression on AD pathology were assessed in F1 progeny. After 1 and 3 months of transgene expression, we found robust increases in tau phosphorylation despite an ∼70–80% reduction in amyloid load and fourfold to sixfold increase in plaque-associated microglia, as well as evidence of greater microglial activation at the site of inflammation. We also found evidence of increased p38 mitogen-activated protein kinase and glycogen synthase kinase-3β activity, which are believed to contribute to tau phosphorylation. Thus, neuroinflammation regulates amyloid and tau pathology in opposing ways, suggesting that it provides a link between amyloid accumulation and changes in tau and raising concerns about the use of immunomodulatory therapies in AD.
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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 [7]
The Results (page unavailable) report unchanged APP, BACE, and β-CTF levels in the studied mice; the Discussion says these findings indicate unaltered secretase activity. This supports no detected change in markers of Aβ production in this mouse model, but not the unqualified claim that IL-1β does not influence Aβ production generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredChronically elevated levels of IL-1β in the brain has been shown to provoke BBB breakdown, to induce the expression of amyloid precursor protein and to exacerbate tau phosphorylation.
“Chronically elevated levels of IL-1β in the brain has been shown to provoke BBB breakdown, to induce the expression of amyloid precursor protein and to exacerbate tau phosphorylation [96], further contributing to AD pathology.”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [96]
The Discussion reports elevated phospho-tau after sustained IL-1β overexpression in an Alzheimer’s mouse model, supporting the tau portion. It reports APP increases only in earlier in vitro or acute-exposure studies; in this study, basal APP expression did not change. The passages found do not report blood–brain barrier breakdown. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIL-1 beta exacerbates tau pathologies and reduces microglial phagocytic activity.
“IL-1 beta was shown to exacerbate tau pathologies [97] and reduce microglial phagocytic activity [92,93,94].”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [97]
Hippocampal IL-1β expression reduces plaques in APP/PS1 and 3xTg-AD models but worsens tauopathy in 3xTg-AD.
“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 [63]
IL-1β treatment or overexpression exacerbates tau phosphorylation through activation of p38 MAPK and/or GSK-3β in neuron-microglia co-cultures and AD model mice.
“IL-1β treatment or overexpression exacerbates tau phosphorylation through the activation of p38 mitogen-activated protein kinase (MAPK) and/or glycogen synthase kinase-3β (GSK-3β) in neuron–microglia co-cultures [161] and AD model mice [162, 163].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [162]
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- Authors
- Ghosh, S., Wu, M. D., Shaftel, S. S., Kyrkanides, S., LaFerla, F. M., Olschowka, J. A., & O'Banion, M. K.
- Affiliations
- University of Rochester Medicine (US)
- Stony Brook University Hospital (US)
- University of California, Irvine (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-03-13
- Volume
- 33
- Issue
- 11
- Pages
- 5053-5064
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3637949
- OpenAlex
- W1984891266
- Semantic Scholar
- ec2b6e7acf81d3154aeddeab03615beea073a3dc
- Cited by
- 390
- References
- 60
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 21 · 2023: 36 · 2022: 33 · 2021: 28 · 2020: 31 · 2019: 36 · 2018: 29 · 2017: 29 · 2016: 31 · 2015: 29 · 2014: 18 · 2013: 13
- FWCI
- 21.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG030149)
- National Institute of General Medical Sciences (T32GM007356)
- 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-1β, Alzheimer's disease, neuroinflammation, tau phosphorylation, amyloid plaques, triple transgenic mouse model, microglial activation, p38 MAPK, glycogen synthase kinase-3β, immunomodulatory therapy
- MeSH terms
- Age Factors, Alzheimer Disease, Analysis of Variance, Animals, Brain, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Mice, Inbred C57BL, Microfilament Proteins, Muscle Proteins, Mutation, Trisaccharides, Tubulin, Immunodeficiency Virus, Feline, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, MAP Kinase Signaling System, Glycogen Synthase Kinase 3, Mice, Interleukin-1beta, Presenilin-1, Amyloid Precursor Protein Secretases
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