LRP1 knockdown aggravates Aβ1-42-stimulated microglial and astrocytic neuroinflammatory responses by modulating TLR4/NF-κB/MAPKs signaling pathways

Exp Cell Res. 2020 Sep 15;394(2):112166. doi: 10.1016/j.yexcr.2020.112166. Epub 2020 Jul 6.

Abstract

Neuroinflammation is an important pathological feature and an early event in the pathogenesis of Alzheimer's disease (AD), which is characterized by activation of microglia and astrocytes. Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic receptor that is abundantly expressed in neurons, microglia, and astrocytes, and plays a critical role in AD pathogenesis. There is increasing evidence to show that LRP1 regulates inflammatory responses by modulating the release of pro-inflammatory cytokines and phagocytosis. However, the effects of LRP1 on β-amyloid protein (Aβ)-induced microglial and astrocytic neuroinflammatory responses and its underlying mechanisms have not been studied in detail. In the present study, knockdown of LRP1 significantly enhanced Aβ1-42-stimulated neuroinflammation by increasing the production of pro-inflammatory cytokines in both BV2 microglial cells and mouse primary astrocytes. Furthermore, it is revealed that LRP1 knockdown further led to the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. The phosphorylation of IκBα, p38, and JNK was significantly up-regulated in LRP1 knockdown BV2 microglial cells and primary astrocytes. Meanwhile, LRP1 knockdown increased expression of the NF-κB p65 subunit in the nucleus while decreased its expression in the cytoplasm. Besides, the upstream signaling adaptor molecules such as toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), and tumor necrosis factor receptor-associated factor 6 (TRAF6) were also further increased. Moreover, blockade of NF-κB, p38, and JNK inhibited the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by the knockdown of LRP1. Taken together, these findings indicated that LRP1 as an effective therapeutic target against AD and other neuroinflammation related diseases.

Keywords: Alzheimer's disease; Low-density lipoprotein receptor-related protein 1; Mitogen-activated protein kinases; Nuclear factor-kappa B; β-amyloid protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Cell Line
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytokines / metabolism
  • Gene Knockdown Techniques
  • Inflammation / pathology*
  • Inflammation Mediators / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • MAP Kinase Signaling System* / drug effects
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism*
  • Microglia / pathology
  • NF-kappa B / metabolism*
  • Peptide Fragments / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Amyloid beta-Peptides
  • Cytokines
  • Inflammation Mediators
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • NF-kappa B
  • Peptide Fragments
  • Protein Kinase Inhibitors
  • Toll-Like Receptor 4
  • amyloid beta-protein (1-42)