LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice
Open accessAbstract
Inflammation and microglial activation are associated with Alzheimer's disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into brains of amyloid precursor protein (APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of Aβ. These studies examined the role of LPS-induced inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to non-transgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received LPS compared to vehicle injections. However, the numbers of silver-positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of Aβ by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients.
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Activated proinflammatory microglia increase tau phosphorylation and drive the spread of tau pathology.
“In contrast, when activated, proinflammatory microglia increase tau phosphorylation50 and drive the spread of tau pathology48.”
From Microglia in neurodegeneration (2018) · cites this paper as [50]
Microglial activation leads to the release of pro-inflammatory factors and induces neuroinflammation, further accelerating the accumulation of hyperphosphorylated tau.
“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 [393]
Activated microglia promote tau phosphorylation and aggregation by activation of the NLRP3 inflammasome in response to amyloid-β.
“Further, activated microglia promote tau phosphorylation and aggregation by activation of the NLRP3 (nucleotide binding oligomerisation domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3) inflammasome in response to amyloid-β [22,23].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [22]
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- Authors
- Lee, D. C., Rizer, J., Selenica, M.-L. B., Reid, P., Kraft, C., Johnson, A., Blair, L., Gordon, M. N., Dickey, C. A., & Morgan, D.
- Affiliations
- University of South Florida (US)
- Corresponding author
- Lee, Daniel C
- Venue
- Journal of Neuroinflammation
- Published
- 2010
- Volume
- 7
- Issue
- 1
- Pages
- 56
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC2949628
- OpenAlex
- W1976856337
- Cited by
- 293
- References
- 39
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 16 · 2023: 19 · 2022: 22 · 2021: 16 · 2020: 26 · 2019: 20 · 2018: 21 · 2017: 16 · 2016: 17 · 2015: 21 · 2014: 17 · 2013: 20 · 2012: 21
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- lipopolysaccharide, neuroinflammation, tau phosphorylation, phosphorylated tau, rTg4510 mice, P301L tau mutation, microglial activation, Alzheimer's disease, tau tangles, arginase-1, Ym1, CD45, anti-inflammatory therapy
- MeSH terms
- Age Factors, Analysis of Variance, Animals, Encephalitis, Frontal Lobe, Hippocampus, Immunohistochemistry, Lipopolysaccharides, Mice, Transgenic, Neurons, Phosphorylation, Silver Staining, Neurofibrillary Tangles, tau Proteins, Microglia, Mice
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