Interleukin-1 Mediates Pathological Effects of Microglia on Tau Phosphorylation and on Synaptophysin Synthesis in Cortical Neurons through a p38-MAPK Pathway
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The presence of tangles of abnormally phosphorylated tau is a characteristic of Alzheimer's disease (AD), and the loss of synapses correlates with the degree of dementia. In addition, the overexpression of interleukin-1 (IL-1) has been implicated in tangle formation in AD. As a direct test of the requirement for IL-1 in tau phosphorylation and synaptophysin expression, IL-1 actions in neuron–microglia cocultures were manipulated. Activation of microglia with secreted β-amyloid precursor protein or lipopolysaccharide elevated their expression of IL-1α, IL-1β, and tumor necrosis factor α (TNFα) mRNA. When such activated microglia were placed in coculture with primary neocortical neurons, a significant increase in the phosphorylation of neuronal tau was accompanied by a decline in synaptophysin levels. Similar effects were evoked by treatment of neurons with recombinant IL-1β. IL-1 receptor antagonist (IL-1ra) as well as anti-IL-1β antibody attenuated the influence of activated microglia on neuronal tau and synaptophysin, but anti-TNFα antibody was ineffective. Some effects of microglial activation on neurons appear to be mediated by activation of p38 mitogen-activated protein kinase (p38-MAPK), because activated microglia stimulated p38-MAPK phosphorylation in neurons, and an inhibitor of p38-MAPK reversed the influence of IL-1β on tau phosphorylation and synaptophysin levels. Our results, together with previous observations, suggest that activated microglia may contribute to neurofibrillary pathology in AD through their production of IL-1, activation of neuronal p38-MAPK, and resultant changes in neuronal cytoskeletal and synaptic elements.
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In neurons, p38α MAPK has been shown to act as an important kinase in inducing IL-1β-mediated hyperphosphorylation of tau.
“Second, in neurons, p38α MAPK has been shown to act as an important kinase in inducing IL-1β-mediated hyperphosphorylation of tau [24, 61].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [24]
The Results and Figure 8 report that IL-1β activated p38-MAPK in cortical neurons and that a p38-MAPK inhibitor suppressed IL-1β-induced tau phosphorylation. The paper identifies the kinase as p38-MAPK, but does not establish that the α isoform specifically mediates the effect. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNeocortical neurons pretreated with SB203580 and then treated with interleukin-1β showed significantly reduced tau phosphorylation and restored synaptophysin levels.
“This is consistent with a previous in vitro study in which neocortical neurons pretreated with the popular-mixed kinase inhibitor SB203580 and then treated with interleukin-1β (IL-1β) showed significantly reduced tau phosphorylation and restored synaptophysin levels [24].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [24]
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 [161]
Activated microglia secrete IL-1β that is critical for enhancing inflammation and prompting neuronal damage via kinase transduction pathways in vitro.
“This demonstrates that activated microglia secrete IL-1β that is critical for enhancing inflammation and prompting neuronal damage via kinase transduction pathways in vitro.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [132]
IL-1 receptor signalling plays a key role in neuroinflammation-induced tau phosphorylation by enhancing the activity of tau kinases including CDK5/p25, GSK3β, and p38-MAPK.
“IL-1 receptor signalling is found to play a key role in neuroinflammation-induced tau phosphorylation by enhancing the activity of tau kinases including cyclin-dependent-like kinase 5/p25 (CDK5/p25), glycogen synthase kinase 3β (GSK3β), and p38 mitogen-activated protein kinase (p38-MAPK)60,61.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [60]
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- Authors
- Li, Y., Liu, L., Barger, S. W., & Griffin, W. S. T.
- Affiliations
- United States Department of Veterans Affairs (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-03-01
- Volume
- 23
- Issue
- 5
- Pages
- 1605-1611
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3833596
- OpenAlex
- W2096158347
- Cited by
- 563
- References
- 35
- Citations by year
- 2026: 25 · 2025: 20 · 2024: 21 · 2023: 29 · 2022: 28 · 2021: 37 · 2020: 30 · 2019: 29 · 2018: 30 · 2017: 28 · 2016: 21 · 2015: 28 · 2014: 34 · 2013: 27 · 2012: 29
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Donald W. Reynolds Foundation
- National Institutes of Health (AG12411)
- National Institute on Aging (AG 12411, P01AG012411)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- interleukin-1, microglia, tau phosphorylation, synaptophysin, p38 MAPK, Alzheimer's disease, neurofibrillary tangles, synaptic loss, interleukin-1 receptor antagonist, TNF-α, amyloid precursor protein, lipopolysaccharide, cortical neurons, neuroinflammation
- MeSH terms
- Animals, Cell Communication, Cells, Cultured, Cerebral Cortex, Interleukin-1, Lipopolysaccharides, Neurons, Phosphorylation, Sialoglycoproteins, Tumor Necrosis Factor-alpha, Signal Transduction, Amyloid beta-Protein Precursor, Synaptophysin, tau Proteins, Rats, Sprague-Dawley, Microglia, Neuroprotective Agents, Coculture Techniques, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mice, Rats, Interleukin 1 Receptor Antagonist Protein
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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