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Accumulation of tau induced in neurites by microglial proinflammatory mediators
Abstract
Aggregated fibrillary microtubule‐associated protein tau is the major component of neurofibrillary tangles in Alzheimer's disease. The exact molecular mechanism of tau aggregation is unknown. Microglial cell activation and migration toward amyloid‐β plaques precede the appearance of dysmorphic neurites and formation of neurofibrillary tangles. Here, we analyzed the accumulation of tau at a distance range of expected spontaneous aggregation by fluorescence lifetime‐based Förster resonance energy transfer in cultured primary murine neurons cotransfected with the human tau gene tagged to the green fluorescent protein variants Citrine (tau‐Citrine) and Cerulean (tau‐Cerulean). No spontaneous accumulation of cotransfected tau‐Citrine and tau‐Cerulean was detected in untreated neurons. Coculture of neurons with activated microglia induced aggregation of tau in neurites. Treatment of neurons with tumor necrosis factor‐α (TNF‐α) stimulated reactive oxygen species generation and resulted in the accumulation of tau‐Citrine and tau‐Cerulean in neurites, which was inhibited by neutralization of TNF and the free radical inhibitor 6‐hydroxy‐2,5,7,8‐tetramethylchromane‐2‐carboxylic acid (Trolox). These data demonstrate that activated microglia and the microglial‐derived proinflammatory cytokine TNF can induce accumulation of the aggregation‐prone tau molecules in neurites via reactive oxygen species.— Gorlovoy, P.,Larionov, S., Pham, T. T. H., Neumann, H. Accumulation of tau induced in neurites by microglial proinflammatory mediators. FASEB J. 23, 2502–2513 (2009)
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“cytokines released by microglia trigger specific intraneuronal signaling that causes tau seeding and hyperphosphorylation [37,38].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [37]
In the citing paper
“They reported that microglial-derived TNF-α was capable of inducing tau aggregation in neurites [150].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [150]
In the citing paper
“Microglial activation led to the release of pro-inflammatory factors and induced neuroinflammation, further accelerating the accumulation of hyperphosphorylated tau.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [394]
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Metadata
- Authors
- Gorlovoy, P., Larionov, S., Pham, T. T. H., & Neumann, H.
- Affiliations
- University of Bonn (DE)
- ORCID
- Neumann, Harald
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2009-03-16
- Volume
- 23
- Issue
- 8
- Pages
- 2502-2513
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2161849052
- Cited by
- 156
- References
- 54
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 14 · 2023: 12 · 2022: 11 · 2021: 9 · 2020: 12 · 2019: 6 · 2018: 13 · 2017: 7 · 2016: 9 · 2015: 11 · 2014: 4 · 2013: 8 · 2012: 14
- FWCI
- 6.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- tau protein, tau aggregation, neurofibrillary tangles, Alzheimer's disease, microglial activation, TNF-α, reactive oxygen species, neurites, inflammatory cytokines, Trolox
- MeSH terms
- Animals, Cells, Cultured, Humans, Neurons, Recombinant Fusion Proteins, Transfection, Tumor Necrosis Factor-alpha, Neurites, Neurofibrillary Tangles, tau Proteins, Reactive Oxygen Species, Microglia, Inflammation Mediators, Coculture Techniques, Fluorescence Resonance Energy Transfer, Multiprotein Complexes, Green Fluorescent Proteins, Mice
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