Involvement of formyl-peptide-receptor-like-1 and phospholipase D in the internalization and signal transduction of amyloid beta 1-42 in glial cells

Neuroscience. 2008 Oct 2;156(2):266-76. doi: 10.1016/j.neuroscience.2008.07.042. Epub 2008 Aug 5.

Abstract

Recent studies suggest that the formyl-peptide-receptor-like-1 (FPRL1) plays an essential role in the inflammatory responses of host defense mechanisms and neurodegenerative disorders such as Alzheimer's disease (AD). We therefore analyzed whether amyloid beta1-42 (Abeta1-42) increased the activity of phospholipase D (PLD) via FPRL1, which is an enzyme involved in the secretion, endocytosis and receptor signaling. PLD activity was determined using a transphosphatidylation assay. The internalization of Abeta1-42 via FPRL1 was visualized using fluorescence microscopy and quantified by ELISA (Enzyme Linked Immunosorbent Assay). Determining receptor activity by extracellular-signal regulated kinases 1/2 (ERK1/2) phosphorylation and cAMP level measurement verified the Abeta1-42-induced activation of FPRL1. We were able to show that Abeta1-42 is rapidly internalized via FPRL1 in astrocytes and microglia. PLD was additionally activated by Abeta1-42 and via FPRL1 in rat glial cells. Furthermore, the ERK1/2 phosphorylation by FPRL1 agonists was dependent on the PLD product phosphatidic acid (PA). Together, these data suggest that PLD plays an important role in the regulation of Abeta1-42-induced endocytosis and FPRL1 receptor signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / agonists
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Brain / cytology
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Endocytosis / drug effects
  • Endocytosis / physiology*
  • Humans
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neuroglia / drug effects
  • Neuroglia / metabolism*
  • Oligopeptides / pharmacology
  • Peptide Fragments / agonists
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology
  • Phospholipase D / metabolism*
  • Rats
  • Receptors, Formyl Peptide / agonists
  • Receptors, Formyl Peptide / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Time Factors
  • tert-Butyl Alcohol / pharmacology

Substances

  • Amyloid beta-Peptides
  • FPR1 protein, human
  • Oligopeptides
  • Peptide Fragments
  • Receptors, Formyl Peptide
  • amyloid beta-protein (1-42)
  • tryptophyl-arginyl-tryptophyl-tryptophyl-tryptophyl-tryptophanamide
  • Cyclic AMP
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases
  • Phospholipase D
  • tert-Butyl Alcohol