Cited by 697Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Lipopolysaccharide-Induced Inflammation Exacerbates Tau Pathology by a Cyclin-Dependent Kinase 5-Mediated Pathway in a Transgenic Model of Alzheimer's Disease

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Kitazawa, Masashi, Oddo, Salvatore, Yamasaki, Tritia R., Green, Kim N., LaFerla, Frank M.·2005·The Journal of Neuroscience

Abstract

Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD). Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a transgenic model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloidβ-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of CNS inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.

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Crossref · 10.1523/jneurosci.2868-05.2005

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  • Promoting microglia activation via LPS- or virus-induced inflammation promotes tau pathology.

    “promoting microglia activation via lipopolysaccharide- or virus-induced inflammation promoted tau pathology [187, 304]”
  • LPS-induced inflammation in mice with amyloidosis or tauopathy increased neuropathology.

    “lipopolysaccharide (a major gram negative bacterial cell wall component)-induced inflammation in mice with amyloidosis or tauopathy increased neuropathology [187, 283]”
  • Pro-inflammatory cytokines released by activated microglia enhance tau pathology through activating tau kinases such as p38 and CDK5.

    “Microglia can also indirectly modulate tau pathogenesis through inflammatory pathways; pro-inflammatory cytokines released by activated microglia can enhance tau pathology through activating tau kinases, such as p38 and CDK5 [430, 431].”
  • Systemic administration of LPS leads to microglial activation in the mouse brain, which results in tau hyperphosphorylation at specific sites.

    “Our and other studies found that systemic administration of lipopolysaccharide (LPS, inducer of inflammation) leads to microglial activation in the mouse brain, which results in tau hyperphosphorylation at specific sites [117, 118].”
  • Chronic intraperitoneal administration of LPS to 3xTg-AD mice for 6 weeks induces marked microglial activation and promotes site-specific tau hyperphosphorylation.

    “chronic intraperitoneal administration of LPS to 3xTg-AD mice[G] for 6-weeks is shown to induce marked microglial activation and promote site-specific tau hyperphosphorylation59.”

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Authors
Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N., & LaFerla, F. M.
Affiliations
University of California, Irvine (US)
Venue
The Journal of Neuroscience
Published
2005-09-28
Volume
25
Issue
39
Pages
8843-8853
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W1976445933
Cited by
697
References
69
Citations by year
2026: 23 · 2025: 27 · 2024: 38 · 2023: 34 · 2022: 28 · 2021: 56 · 2020: 36 · 2019: 30 · 2018: 44 · 2017: 26 · 2016: 36 · 2015: 47 · 2014: 47 · 2013: 33 · 2012: 42
FWCI
14.18
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • National Institutes of Health
  • National Institute on Aging (AG0212982, AG17968, R01AG017968)
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
Alzheimer's disease, lipopolysaccharide, neuroinflammation, microglial activation, tau hyperphosphorylation, cyclin-dependent kinase 5, roscovitine, amyloid plaques, neurofibrillary tangles, 3xTg-AD mice, hippocampus, APP processing
MeSH terms
Roscovitine, Aging, Alzheimer Disease, Animals, Disease Models, Animal, Encephalitis, Enzyme Activation, Female, Hippocampus, Lipopolysaccharides, Male, Mice, Transgenic, Neural Pathways, Phosphorylation, Purines, tau Proteins, Microglia, Tauopathies, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 5, Mice

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