Loss of tau rescues inflammation-mediated neurodegeneration

Nicole Maphis, Guixiang Xu, Olga N. Kokiko-cochran, Astrid Cardona, Richard M. Ransohoff, Bruce T. Lamb, Kiran Bhaskar

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease (AD) and related tauopathies. Activated microglia spatially coexist with microtubule associated protein tau (Mapt or tau)-burdened neurons in the brains of human AD and non-AD tauopathies. Numerous studies have suggested that neuroinflammation precedes tau pathology and that induction or blockage of neuroinflammation via lipopolysaccharide (LPS) or anti-inflammatory compounds (such as FK506) accelerate or block tau pathology, respectively in several animal models of tauopathy. We have previously demonstrated that microglia-mediated neuroinflammation via deficiency of the microglia-specific chemokine (fractalkine) receptor, CX3CR1, promotes tau pathology and neurodegeneration in a mouse model of LPS-induced systemic inflammation. Here, we demonstrate that tau mediates the neurotoxic effects of LPS in Cx3cr1-/- mice. First, Mapt+/+ neurons displayed elevated levels of Annexin V (A5) and TUNEL (markers of neurodegeneration) when co-cultured with LPS-treated Cx3cr1-/-microglia, which is rescued in Mapt-/- neurons. Second, a neuronal population positive for phospho-S199 (AT8) tau in the dentate gyrus is also positive for activated or cleaved caspase (CC3) in the LPS-treated Cx3cr1-/- mice. Third, genetic deficiency for tau in Cx3cr1-/- mice resulted in reduced microglial activation, altered expression of inflammatory genes and a significant reduction in the number of neurons positive for CC3 compared to Cx3cr1-/- mice. Finally, Cx3cr1-/- mice exposed to LPS displayed a lack of inhibition in an open field exploratory behavioral test, which is rescued by tau deficiency. Taken together, our results suggest that pathological alterations in tau mediate inflammation-induced neurotoxicity and that deficiency of Mapt is neuroprotective. Thus, therapeutic approaches towards either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.

Original languageEnglish (US)
Article number196
JournalFrontiers in Neuroscience
Volume9
Issue numberMAY
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Alzheimer's disease
  • CX3CR1 knockout and neurodegeneration
  • Cx3cr1
  • Fractalkine receptor
  • Microglia
  • Microtubule associated protein tau (MAPT)
  • Neuroinflammation
  • Tau knockout
  • Tau protein
  • Tauopathies

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Maphis, N., Xu, G., Kokiko-cochran, O. N., Cardona, A., Ransohoff, R. M., Lamb, B. T., & Bhaskar, K. (2015). Loss of tau rescues inflammation-mediated neurodegeneration. Frontiers in Neuroscience, 9(MAY), [196]. https://doi.org/10.3389/fnins.2015.00196