Apolipoprotein E-Containing Lipoproteins Protect Neurons from Apoptosis via a Signaling Pathway Involving Low-Density Lipoprotein Receptor-Related Protein-1

• Published in: The Journal of neuroscience Vol. 27; no. 8; pp. 1933 - 1941
• Main Authors: Hayashi, Hideki, Campenot, Robert B, Vance, Dennis E, Vance, Jean E
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 21.02.2007; Society for Neuroscience
• Subjects: Animals; Apolipoprotein E3 - physiology; Apolipoprotein E4 - physiology; Apolipoproteins E - physiology; Apoptosis - physiology; Cells, Cultured; Cytoprotection - physiology; Lipoproteins - metabolism; Lipoproteins - physiology; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; Neurons - physiology; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells - physiology; Signal Transduction - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5471-06.2007

Apolipoprotein E (apoE)-containing lipoproteins (LPs) are secreted by glia and play important roles in lipid homeostasis in the CNS. Glia-derived LPs also promote synaptogenesis and stimulate axon growth of CNS neurons. Here, we provide evidence that glia-derived LPs protect CNS neurons from apoptosis by a receptor-mediated signaling pathway. The protective effect was greater for apolipoprotein E3 than for apolipoprotein E4, the expression of which is a risk factor for Alzheimer's disease. The anti-apoptotic effect of LPs required the association of apolipoprotein E with lipids but did not require cholesterol. Apoptosis was not prevented by lipids alone or by apoA1- or apoJ-containing lipoproteins. The prevention of neuronal apoptosis was initiated after the binding of LPs to the low-density lipoprotein receptor-related protein (LRP), a multifunctional receptor of the low-density lipoprotein receptor family. We showed that inhibition of LRP activation, by treatment of neurons with receptor-associated protein or anti-LRP antibodies, or by LRP gene-silencing experiments, reduced the protective effect of LPs. Furthermore, another LRP ligand, alpha2-macroglobulin, also protected the neurons from apoptosis. After binding to LRP, LPs initiate a signaling pathway that involves activation of protein kinase Cdelta and inactivation of glycogen synthase kinase-3beta. These findings indicate the potential for using glial lipoproteins or an activator of the LRP signaling pathway for treatment for neurodegenerative disorders such as Alzheimer's disease.