Apolipoproteins D and E3 exert neurotrophic and synaptogenic effects in dorsal root ganglion cell cultures

Neuroscience. 2009 Aug 18;162(2):282-91. doi: 10.1016/j.neuroscience.2009.04.073. Epub 2009 May 3.

Abstract

Co-cultures of 3T3-L1 adipocytes with neurons from the rat dorsal root ganglia (DRG) showed enhanced neuritogenesis and synaptogenesis. Microarray analysis for upregulated genes in adipocyte/DRG co-cultures currently points to apolipoproteins D and E (ApoD, ApoE) as influential proteins. We therefore tested adipocyte-secreted cholesterol and the carrier proteins ApoD and ApoE3. Cholesterol, ApoD, and ApoE3 each increased neurite outgrowth and upregulated the expression of presynaptic synaptophysin and synaptotagmin, as well as the postsynaptic density protein 95. The neurotrophic effects of ApoD and ApoE3 were associated with an increased expression of the low-density lipoprotein receptor and apolipoprotein E receptor 2. Simultaneous treatment with receptor-associated protein, an apolipoprotein receptor antagonist, inhibited the neurotrophic function of both apolipoproteins. The application of ApoD, ApoE3, and cholesterol to DRG cell cultures corresponded with increased expression of the chemokine stromal cell-derived factor 1 and its receptor CXC chemokine receptor 4 (CXCR4). Surprisingly, the inhibition of CXCR4 by the antagonistic drug AMD3100 decreased the apolipoprotein/cholesterol dependent neurotrophic effects. We thus assume that apolipoprotein-induced neuritogenesis in DRG cells interferes with CXCR4 signaling, and that adipocyte-derived apolipoproteins might be helpful in nerve repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipokines / biosynthesis
  • Animals
  • Apolipoprotein E3 / pharmacology
  • Apolipoprotein E3 / physiology*
  • Apolipoproteins D / pharmacology
  • Apolipoproteins D / physiology*
  • Cells, Cultured
  • Chemokine CXCL12 / biosynthesis
  • Cholesterol / pharmacology
  • Cholesterol / physiology
  • Coculture Techniques
  • Disks Large Homolog 4 Protein
  • Ganglia, Spinal / cytology*
  • Heterocyclic Compounds / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • LDL-Receptor Related Protein-Associated Protein / pharmacology
  • Membrane Proteins / biosynthesis
  • Neurites / physiology
  • Neurons / drug effects
  • Neurons / physiology*
  • Rats
  • Rats, Inbred WF
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / biosynthesis
  • Receptors, Lipoprotein / antagonists & inhibitors
  • Receptors, Lipoprotein / metabolism
  • Synapses / drug effects
  • Synapses / physiology*
  • Synaptophysin / biosynthesis
  • Synaptotagmins / biosynthesis
  • Up-Regulation

Substances

  • Adipokines
  • Apolipoprotein E3
  • Apolipoproteins D
  • Chemokine CXCL12
  • Cxcr4 protein, rat
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Heterocyclic Compounds
  • Intracellular Signaling Peptides and Proteins
  • LDL-Receptor Related Protein-Associated Protein
  • Membrane Proteins
  • Receptors, CXCR4
  • Receptors, Lipoprotein
  • Synaptophysin
  • Synaptotagmins
  • Cholesterol
  • plerixafor