IKKβ deficiency in myeloid cells ameliorates Alzheimer's disease-related symptoms and pathology

Yang Liu, Xu Liu, Wenlin Hao, Yann Decker, Robert Schomburg, Livia Fülöp, Manolis Pasparakis, Michael D. Menger, Klaus Fassbender

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18 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposits and microglia-dominated inflammatory activation. Innate immune signaling controls microglial inflammatory activities and Aβ clearance. However, studies examining innate immunity in Aβ pathology and neuronal degeneration have produced conflicting results. In this study, we investigated the pathogenic role of innate immunity in AD by ablating a key signaling molecule, IKKβ, specifically in the myeloid cells of TgCRND8 APP-transgenic mice. Deficiency of IKKβ in myeloid cells, especially microglia, simultaneously reduced inflammatory activation and Aβ load in the brain and these effects were associated with reduction of cognitive deficits and preservation of synaptic structure proteins. IKKβ deficiency enhanced microglial recruitment to Aβ deposits and facilitated Aβ internalization, perhaps by inhibiting TGF-β-SMAD2/3 signaling, but did not affect Aβ production and efflux. Therefore, inhibition of IKKβ signaling in myeloid cells improves cognitive functions in AD mice by reducing inflammatory activation and enhancing Aβ clearance. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying AD progression.

Original languageEnglish
Pages (from-to)12982-12999
Number of pages18
JournalJournal of Neuroscience
Volume34
Issue number39
DOIs
Publication statusPublished - Sep 24 2014

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Keywords

  • Alzheimer’s disease
  • Endocytosis
  • Inflammation
  • Microglia
  • NF-κB
  • Neurodegeneration

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Liu, Y., Liu, X., Hao, W., Decker, Y., Schomburg, R., Fülöp, L., Pasparakis, M., Menger, M. D., & Fassbender, K. (2014). IKKβ deficiency in myeloid cells ameliorates Alzheimer's disease-related symptoms and pathology. Journal of Neuroscience, 34(39), 12982-12999. https://doi.org/10.1523/JNEUROSCI.1348-14.2014