Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease

Masashi Kitazawa, Salvatore Oddo, Tritia R. Yamasaki, Kim N. Green, Frank M. LaFerla

Research output: Contribution to journalArticle

419 Citations (Scopus)

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 amyloid β-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.

Original languageEnglish (US)
Pages (from-to)8843-8853
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number39
DOIs
StatePublished - Sep 28 2005
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 5
Lipopolysaccharides
Alzheimer Disease
Pathology
Inflammation
Microglia
Amyloid beta-Protein Precursor
Amyloid Plaques
Hippocampus
Phosphorylation
Peptides
Brain

Keywords

  • Amyloid
  • APP
  • cdk5
  • Interleukin
  • Microglia
  • Tau
  • Transgenic

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. / Kitazawa, Masashi; Oddo, Salvatore; Yamasaki, Tritia R.; Green, Kim N.; LaFerla, Frank M.

In: Journal of Neuroscience, Vol. 25, No. 39, 28.09.2005, p. 8843-8853.

Research output: Contribution to journalArticle

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