Role of apolipoprotein E receptors in regulating the differential in vivo neurotrophic effects of apolipoprotein E.
Apolipoprotein E (apoE) is known to bind to at least five receptors, including the low-density lipoprotein (LDL) receptor-related protein (LRP), very low density LDL receptor (VLDL-R), LDL-R, apoE receptor 2 (apoER2), and megalin/gp330. In this context, the main objective of the present study was to better understand the contributions of LRP and LDL-R to the in vivo neurotrophic effects of apoE. For this purpose, apoE-deficient and receptor-associated protein (RAP)-deficient mice were infused with recombinant apoE3, RAP, or saline. Infusion of apoE3 into apoE-deficient mice resulted in amelioration of degenerative alterations of pyramidal neurons, but had no effect on somatostatin-producing interneurons. In contrast, infusion of apoE3 into RAP-deficient mice resulted in amelioration of degenerative alterations of somatostatin-producing interneurons. LRP and LDL-R levels were significantly reduced in RAP-deficient mice, but significantly increased in the apoE-deficient mice. In contrast, levels of apoE were reduced in the RAP-deficient mice compared to wildtype controls, suggesting that neurotrophic effects of apoE3 in the RAP-deficient mice were related to a combined deficit in endogenous apoE and selected apoE receptors. Furthermore, in apoE-deficient mice, infusion of apoE3 had a neurotrophic effect on somatostatin-producing interneurons only when combined with RAP, suggesting that increased expression of apoE receptors in apoE-deficient mice prevented apoE from rescuing somatostatin-producing neurons. This study supports the contention that some of the in vivo neurotrophic effects of apoE are mediated by LRP and LDL-R and that a critical balance between levels of apoE and its receptors is necessary for the differential neurotrophic effects to appear.
Veinbergs
I
I
Department of Neurosciences, University of California-San Diego, La Jolla, CA 92093-0624, USA.
Van Uden
E
E
Mallory
M
M
Alford
M
M
McGiffert
C
C
DeTeresa
R
R
Orlando
R
R
Masliah
E
E
D000818:Animals; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D026541:Heymann Nephritis Antigenic Complex; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019579:Neocortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism
D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D026541:Heymann Nephritis Antigenic Complex; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009414:Nerve Growth Factors; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D013004:Somatostatin