Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease

Silke Walter, Maryse Letiembre, Yang Liu, Holger Heine, Botond Penke, Wenlin Hao, Barbara Bode, Nicole Manietta, Jessica Walter, Walter Schulz-Schüffer, Klaus Faßbender

Research output: Contribution to journalArticle

316 Citations (Scopus)

Abstract

Microglial activation is a key feature in Alzheimer's disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFα and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer's disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer's disease.

Original languageEnglish
Pages (from-to)947-956
Number of pages10
JournalCellular Physiology and Biochemistry
Volume20
Issue number6
DOIs
Publication statusPublished - Jan 1 2007

Keywords

  • Alzheimer's disease
  • Amyloid peptide
  • CD14
  • Microglia
  • Neuroinflammation
  • TLR2
  • TLR4

ASJC Scopus subject areas

  • Physiology

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  • Cite this

    Walter, S., Letiembre, M., Liu, Y., Heine, H., Penke, B., Hao, W., Bode, B., Manietta, N., Walter, J., Schulz-Schüffer, W., & Faßbender, K. (2007). Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cellular Physiology and Biochemistry, 20(6), 947-956. https://doi.org/10.1159/000110455