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The Journal of Neuroscience, February 21, 2007, 27(8):1933-1941; doi:10.1523/JNEUROSCI.5471-06.2007

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

Hideki Hayashi,^1,2 Robert B. Campenot,³ Dennis E. Vance,^1,4 and Jean E. Vance^1,2

¹Group on Molecular and Cell Biology of Lipids and ²Departments of Medicine, ³Cell Biology, and ⁴Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

Correspondence should be addressed to Jean E. Vance, 332 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. Email: jean.vance{at}ualberta.ca

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, ₂-macroglobulin, also protected the neurons from apoptosis. After binding to LRP, LPs initiate a signaling pathway that involves activation of protein kinase C and inactivation of glycogen synthase kinase-3ß. 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.

Key words: apolipoprotein E; apoptosis; glia; lipoproteins; low-density lipoprotein receptor-related protein; glycogen synthase kinase-3ß

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Received May 18, 2006; accepted Jan. 9, 2007.

Correspondence should be addressed to Jean E. Vance, 332 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. Email: jean.vance{at}ualberta.ca

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