β-amyloid binds to microglia Dectin-1 to induce inflammatory response in the pathogenesis of Alzheimer's disease

Int J Biol Sci. 2023 Jun 19;19(10):3249-3265. doi: 10.7150/ijbs.81900. eCollection 2023.

Abstract

Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). In the early stages of the inflammation response, pattern recognition receptors (PRRs) play a key role in clearing damaged cells and defending against infection by recognizing endogenous and exogenous ligands. However, the regulation of pathogenic microglial activation and its role in AD pathology remains poorly understood. Here we showed that a pattern recognition receptor called Dectin-1, expressed on microglia, mediates the pro-inflammatory responses of beta-amyloid (Aβ). Knockout of Dectin-1 reduced Aβ1-42 (Aβ42)-induced microglial activation, inflammatory responses, and synaptic and cognitive deficits in Aβ42-infused AD mice. Similar results were obtained in the BV2 cell model. Mechanistically, we showed that Aβ42 could directly bind to Dectin-1, causing Dectin-1 homodimerization and activating downstream spleen tyrosine kinase (Syk)/nuclear factor-κB (NF-κB) signaling pathway to induce the expression of inflammatory factors and, in turn, AD pathology. These results suggest the important role of microglia Dectin-1 as a new direct receptor for Aβ42 in microglial activation and AD pathology and provide a potential therapeutic strategy for neuroinflammation in AD.

Keywords: Alzheimer's disease; Dectin-1; Microglia; Neuroinflammation; β-amyloid.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Mice
  • Mice, Knockout
  • Microglia / metabolism
  • Neuroinflammatory Diseases

Substances

  • Amyloid beta-Peptides
  • dectin 1
  • Clec7a protein, mouse