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Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis

Isabel Lastres-Becker, Nadia G. Innamorato, Tomasz Jaworski, Alberto Rábano, Sebastian Kügler, Fred Van Leuven, Antonio Cuadrado
DOI: http://dx.doi.org/10.1093/brain/awt323 78-91 First published online: 25 November 2013

Summary

The chemokine fractalkine modulates microglial responses in neurodegenerative diseases, including tauopathies, but the mechanistic processes and their relevance in human brain pathologies is not yet known. Here, we show that hippocampal HT22 cells expressing human TAUP301L mutant protein produce fractalkine, which in microglia activates AKT, inhibits glycogen synthase kinase-3β and upregulates the transcription factor NRF2/NFE2L2 and its target genes including heme oxygenase 1. In a mouse model of tauopathy based on stereotaxic delivery in hippocampus of an adeno-associated viral vector for expression of TAUP301L, we confirmed that tau-injured neurons express fractalkine. NRF2- and fractalkine receptor-knockout mice did not express heme oxygenase 1 in microglia and exhibited increased microgliosis and astrogliosis in response to neuronal TAUP301L expression, demonstrating a crucial role of the fractalkine/NRF2/heme oxygenase 1 pathway in attenuation of the pro-inflammatory phenotype. The hippocampus of patients with Alzheimer’s disease also exhibits increased expression of fractalkine in TAU-injured neurons that recruit microglia. These events correlated with increased levels of NRF2 and heme oxygenase 1 proteins, suggesting an attempt of the diseased brain to limit microgliosis. Our combined results indicate that fractalkine mobilizes NRF2 to limit over-activation of microglia and identify this new target to control unremitting neuroinflammation in tauopathies.

  • adeno-associated virus
  • oxidative stress
  • Alzheimer’s disease
  • neuroimmunology
  • Abbreviations
    ARE
    antioxidant response element
    HO-1
    heme oxygenase 1
    NRF2
    nuclear factor (erythroid-derived 2)-like 2
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