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Apolipoprotein E-Containing Lipoproteins Protect Neurons from Apoptosis via a Signaling Pathway Involving Low-Density Lipoprotein Receptor-Related Protein-1
Abstract
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, α 2-macroglobulin, also protected the neurons from apoptosis. After binding to LRP, LPs initiate a signaling pathway that involves activation of protein kinase Cδ and inactivation of glycogen synthase kinase-3β. 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.
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ApoE can both load and unload cholesterol from cells, including neurons.
“ApoE can both load and unload cholesterol from cells, including neurons (41–43) (see also SI Appendix).”
From Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol (2021) · cites this paper as [43]
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“In addition, binding APOE-LPs to LRP initiates the prevention of neuronal apoptosis [102].”
BackgroundMacrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation
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Metadata
- Authors
- Hayashi, H., Campenot, R. B., Vance, D. E., & Vance, J. E.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-02-21
- Volume
- 27
- Issue
- 8
- Pages
- 1933-1941
- ISSN
- 0270-6474
- 1529-2401
- Cited by
- 146
- References
- 4
- Language
- en
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