In a recent paper in JBC, Fryer and coworkers showed that the LDLR regulates ApoE levels in vitro and in vivo. The authors have previously shown that recombinant ApoE binds LRP but not LDLR. In a recent paper by Ruiz and coworkers (2005), the idea of receptor specificity was also raised, where LRP receptor, like LDLR, prefers lipid-bound forms of recombinant ApoE. However, here they show that LDLR, and not LRP or any other member of the LDL-receptor family, is responsible for astrocyte-secreted ApoE3 uptake and degradation. In addition, recombinant ApoE purified under reducing conditions was not a ligand for LRP, although it was a ligand for VLDLR.

In LDLR-/- mice, murine ApoE levels are elevated both in CSF and in PBS extracted cortex. LDLR-/- X PDAPP(V717F) mice did not show any changes in either Aβ1-40 or 1-42 levels or deposition. However, CSF and cortical ApoE levels were not measured here. Previously, somewhat contrary reports of the role of E3 and E4 in Aβ clearance have been described. In a seminal study, Bales and coworkers demonstrated the ApoE-/- X PDAPP mice...  Read more

In a recent paper in JBC, Fryer and coworkers showed that the LDLR regulates ApoE levels in vitro and in vivo. The authors have previously shown that recombinant ApoE binds LRP but not LDLR. In a recent paper by Ruiz and coworkers (2005), the idea of receptor specificity was also raised, where LRP receptor, like LDLR, prefers lipid-bound forms of recombinant ApoE. However, here they show that LDLR, and not LRP or any other member of the LDL-receptor family, is responsible for astrocyte-secreted ApoE3 uptake and degradation. In addition, recombinant ApoE purified under reducing conditions was not a ligand for LRP, although it was a ligand for VLDLR.

In LDLR-/- mice, murine ApoE levels are elevated both in CSF and in PBS extracted cortex. LDLR-/- X PDAPP(V717F) mice did not show any changes in either Aβ1-40 or 1-42 levels or deposition. However, CSF and cortical ApoE levels were not measured here. Previously, somewhat contrary reports of the role of E3 and E4 in Aβ clearance have been described. In a seminal study, Bales and coworkers demonstrated the ApoE-/- X PDAPP mice resulted in a significant decrease in amyloid burden (Bales et al., 1997). However, these mice crossed with GFAP-ApoE3 or E4 mice resulted initially in a further reduction of Aβ deposition (Holtzman et al., 1999), although animals aged beyond 12 months did exhibit Aβ deposition (ApoE4 > ApoE3) (Holtzman et al., 2000). A targeted replacement mouse expressing the different human ApoE isoforms (ApoE-TR), under the control of the endogenous mouse ApoE promoter, is perhaps the most relevant transgenic model available to study the effect of human ApoE isoform in the context of Aβ deposition. Here, ApoE-TR X LDLR-/- mice resulted in an increase in CSF ApoE3 and E4, almost to the level of ApoE2-TR mice.

LDLR-/- mice are known to have significantly increased plasma cholesterol levels, but in the current paper, the authors reported no difference in hippocampal or CSF cholesterol. In the LDLR-/- X ApoE-TR mice, ApoE3 showed a trend toward reducing cholesterol levels in the cortex. Further study will be needed to determine if there is an ApoE isoform-specific “rescue” effect on CNS cholesterol levels in these mice.

A more detailed study of the effect of LDLR on Aβ deposition and human ApoE isoform and cholesterol levels will be possible in an ApoE-TR X PDAPP/LDLR-/- mouse. It will also be necessary to further investigate the interaction between LDLR and LRP, as ApoE-mediated clearance of Aβ via LRP has previously been observed both in vitro and in vivo by the authors of the current paper.

References:
Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ, Piccardo P, Ghetti B, Paul SM. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997 Nov;17(3):263-4. No abstract available. Abstract

Holtzman DM, Bales KR, Wu S, Bhat P, Parsadanian M, Fagan AM, Chang LK, Sun Y, Paul SM. Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. J Clin Invest. 1999 Mar;103(6):R15-R21. Abstract

Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D, Paul SM. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7. Abstract

Ruiz J, Kouiavskaia D, Migliorini M, Robinson S, Saenko EL, Gorlatova N, Li D, Lawrence D, Hyman BT, Weisgraber KH, Strickland DK. Characterization of the apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J Lipid Res. 2005 May 1; [Epub ahead of print] Abstract

View all comments by Kristina Holmberg

The study by Fryer et al. answers fundamental questions regarding the role of LDL receptor (LDL-r) family members in the regulation of apolipoprotein E (ApoE) in the brain [1]. Characterizing lipid physiology in the brain is critical for understanding Alzheimer disease (AD), given the role of ApoE4 as a risk factor for AD, the modulation of amyloid precursor protein (APP) metabolism by statin lipid-lowering drugs, and the involvement of ApoE and ApoE receptors in CNS injury and repair processes. Pitas first demonstrated that astrocytes take up ApoE incorporated in HDL-type particles via LDL-r [2], but the relative contributions of the other LDL-r family members LRP, VLDL-r, ApoER2, and gp330 have been less extensively studied. Using CHO cells transfected with the different ApoE receptors, Fryer demonstrated that only LDL-r significantly took up astrocyte-derived ApoE-containing lipoproteins. The physiologic relevance of LDL-r as the primary ApoE receptor in brain was supported by in vivo experiments. Mice lacking LDL-r accumulated higher levels of ApoE; when LDL-r-null mice were...  Read more

The study by Fryer et al. answers fundamental questions regarding the role of LDL receptor (LDL-r) family members in the regulation of apolipoprotein E (ApoE) in the brain [1]. Characterizing lipid physiology in the brain is critical for understanding Alzheimer disease (AD), given the role of ApoE4 as a risk factor for AD, the modulation of amyloid precursor protein (APP) metabolism by statin lipid-lowering drugs, and the involvement of ApoE and ApoE receptors in CNS injury and repair processes. Pitas first demonstrated that astrocytes take up ApoE incorporated in HDL-type particles via LDL-r [2], but the relative contributions of the other LDL-r family members LRP, VLDL-r, ApoER2, and gp330 have been less extensively studied. Using CHO cells transfected with the different ApoE receptors, Fryer demonstrated that only LDL-r significantly took up astrocyte-derived ApoE-containing lipoproteins. The physiologic relevance of LDL-r as the primary ApoE receptor in brain was supported by in vivo experiments. Mice lacking LDL-r accumulated higher levels of ApoE; when LDL-r-null mice were crossed with mice overexpressing different human ApoE isoforms, mice lacking LDL-r accumulated higher levels of ApoE3 and ApoE4, but not ApoE2, which binds poorly to the LDL-r.

This paper complements a recent paper by Ruiz et al. in characterizing the binding specificity of ApoE to VLDL-r and LRP [3]. LDL-r requires lipid-bound ApoE and has a low affinity for ApoE2. Using in vitro binding assays, Ruiz demonstrated that LRP also preferred lipid-bound ApoE, but had affinity for all three ApoE isoforms. In addition to binding all isoforms of ApoE, VLDL-r also bound lipid-free ApoE. Together, these papers indicate that ApoE physiology is modulated by ApoE isoform, sialylation, disulfide dimerization, and lipid association that affects receptor interactions in the brain. The LDL-r receptor is the principal regulator of steady-state ApoE levels in the brain; since LRP and VLDL-r are upregulated in glia in CNS injury, it would be interesting to examine whether ApoE released in lesion models, for instance, is LRP or VLDL-r receptor-competent.

References:
1. Fryer JD, Demattos RB, McCormick LM, O'dell MA, Spinner ML, Bales KR, Paul SM, Sullivan PM, Parsadanian M, Bu G, Holtzman DM. The low-density lipoprotein receptor regulates the level of CNS human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. J Biol Chem. 2005 May 11; [Epub ahead of print] Abstract

2. Pitas RE, Boyles JK, Lee SH, Foss D, and Mahley RW. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta. 1987 Jan 13;917(1):148-61. Abstract

3. Ruiz J, Kouiavskaia D, Migliorini M, Robinson S, Saenko EL, Gorlatova N, Li D, Lawrence D, Hyman BT, Weisgraber KH, Strickland DK. Characterization of the ApoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J Lipid Res. 2005 May 1; [Epub ahead of print] Abstract

View all comments by Michael Irizarry