Neurobiol Lipids 4, 2 (16 December 2005) find out how to cite this article

Michael C. Irizarry

Alzheimer's Disease Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, East Building 114, Room 2010, 114 16th Street Charlestown, MA 02129, USA
email: mirizarry@partners.org, fax: (617) 724-1480

Submitted: 2 June 2005; Published online: 16 December, 2005  | Article readership
Copyright © 2005 M C Irizarry, Licensee Neurobiology of Lipids

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Apolipoprotein E (apoE) in the brain is implicated in Alzheimer disease (AD) risk, lipid metabolism, neural development, and response to injury.  The effects of apoE are mediated by receptors of the low-density lipoprotein receptor (LDL-r) family.  Recent studies in cell culture and LDL-r knockout mice suggest that LDL-r is the major receptor influencing brain apoE levels.  Many factors affect the receptor binding characteristics of apoE, including the apoE isoform and the lipid content of apoE-containing lipoprotein particles.  Clarifying the specific apoE receptors involved in the diverse actions of apoE in the central nervous system can identify therapeutic targets to modify the risk of AD associated with the APOE e4 allele and hypercholesterolemia.

Apolipoprotein E (apoE) in the brain is implicated in Alzheimer disease (AD) risk, lipid metabolism, neural development, and response to injury.  The effects of apoE are mediated by receptors of the low-density lipoprotein receptor (LDL-r) family.  Recent studies in cell culture and LDL-r knockout mice suggest that LDL-r is the major receptor influencing brain apoE levels [1].  Many factors affect the receptor binding characteristics of apoE, including the apoE isoform and the lipid content of apoE-containing lipoprotein particles.  Clarifying the specific apoE receptors involved in the diverse actions of apoE in the central nervous system can identify therapeutic targets to modify the risk of AD associated with the APOE e4 allele and hypercholesterolemia.

Characterizing lipid physiology in the brain is critical for understanding Alzheimer disease (AD) given the role of the apolipoprotein E (APOE) e4 allele as a risk factor for AD, the modulation of amyloid precursor protein (APP) metabolism by statin lipid-lowering drugs, and the increased expression of apoE and apoE receptors in response to central nervous system injury. The recent study by Fryer, et al., answers fundamental questions about the functions of LDL-r family members in the regulation of apoE and cholesterol in the brain [1].

ApoE in the nervous system participates in lipid transport, development, synaptogenesis, neurite regeneration, and amyloid b protein (Ab) metabolism [2]. These effects are mediated by interactions with receptors of the low density lipoprotein receptor (LDL-r) family. At least 7 LDL-r family members are expressed in the brain: LDL-r, very low density lipoprotein receptor (VLDL-r), LDL-r related protein (LRP), glycoprotein 330 (gp330/megalin), apolipoprotein E receptor 2 (apoER2/LRP8), multiple epidermal growth factors domains 7 (MEGF7/LRP4), and LRP1B. These are multifunctional receptors containing transmembrane, ligand-binding, epidermal growth factor (EGF), O-linked sugar, and NPxY domains [3]. They display varying affinities for the different apoE isoforms as well as for other ligands, including proteins involved in lipoprotein metabolism and protease/protease inhibitor complexes [4]. The relative importance of each apoE receptor in mediating the distinct effects of apoE in the nervous system is an active area of investigation.

Knockout models of apoE and apoE receptors provide insight into novel roles of these proteins, especially in brain development and Ab metabolism. ApoER2 and VLDL-r double knockout mice had cerebellar and cortical dysgenesis attributed to dysfunction in the reelin pathway [5]. Mice lacking gp330 had holoprosencephaly with impaired sonic hedgehog and bone morphogenic protein 4 signaling [6]. The effects of apoE on Ab deposition were demonstrated in crosses between apoE knockout mice and APP transgenic mice [7, 8, 9]. Given the ubiquitous distribution of LDL-r and its prominent role in lipid metabolism, it is surprising that absence of functional LDL-r in mice and humans has minimal neurological effects [3]. Synaptic loss was reported in LDL-r knockout mice, but to a lesser extent than in apoE knockout mice [10]. In the peripheral circulation, LDL-r knockout mice exhibited hypercholesterolemia and accumulation of apoE in the intermediate and low density lipoprotein fraction [3]. There was no accumulation of brain cholesterol in LDL-r knockout mice, confirming that brain cholesterol clearance mechanisms were unaffected and that de novo neuronal and glial cholesterol synthesis was sufficient [11]. On the other hand, the accumulation of apoE in the brains of LDL-r knockout mice provides convincing evidence that LDL-r is important for apoE homoestasis in the brain [1].

ApoE is released by astrocytes and microglia in high-density lipoprotein (HDL)-like particles [12].  Pitas, et al., first demonstrated that astrocytes take up apoE incorporated in HDL-type particles via LDL-r [13], but the relative contributions of the other LDL-r family members to apoE endocytosis have been less extensively studied. ApoE-containing lipoproteins provide cholesterol to neurons during neurite outgrowth and synaptogenesis in vitro  [14, 15, 16]. ApoE and apoE receptors are upregulated at sites of nervous system injury, further supporting a role in lipid recycling during periods of repair in vivo  [17].  These effects are inhibited by receptor-associated protein (RAP), a pan-inhibitor of the LDL-r family of receptors  [15].

Using Chinese hamster ovary (CHO) cells transfected with LDL-r, an LRP mini-receptor, apoER2, and VLDL-r, Fryer, et al., found that only cells with LDL-r significantly endocytosed 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 in cerebrospinal fluid (CSF) and brain homogenates.  When LDL-r null mice were crossed with mice overexpressing different  human apoE isoforms, mice lacking LDL-r had markedly elevated CSF levels of apoE3 and apoE4, but not apoE2, which binds poorly to the LDL-r [1].

These studies specifically focused on astrocyte-derived HDL-type lipoproteins. However, apoE physiology is modulated by apoE isoform, sialylation, disulfide dimerization, and lipid association that affect receptor interactions [18]. Ruiz, et al., recently further characterized the binding specificity of apoE to VLDL-r and LRP [19]. LDL-r requires lipid-bound apoE and has a low affinity for apoE2. By in vitro binding assays, LRP also preferred lipid-bound apoE, but had affinity for all three apoE isoforms. In addition to binding all isoforms of apoE, VLDL-r further recognized lipid-free apoE. These distinct receptor specificities could have functional consequences in the nervous system. While LDL-r receptor is the principal regulator of steady state apoE levels in the brain, the lipid composition of apoE-containing lipoprotein particles released in the setting of degenerating membranes could differ from resting-state astrocyte-derived lipoproteins [20]. 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.

The implications of these findings for APP metabolism and Ab deposition in animal models of AD requires further investigation. A 50 % elevation of brain apoE levels in the LDL-r knockout mice was insufficient to affect soluble, insoluble, and deposited Ab levels in APP transgenic mice [1]. However, crosses of APP transgenic mice with apoE knockout mice and human apoE3- and apoE4-overexpressing mice demonstrated that apoE influenced the amount, form, and anatomical distribution of cerebral Ab deposition [7, 8, 9]. Thus, other receptors such as LRP may mediate the effect of apoE on AD risk [21], reflecting the complex interplay between Ab, cholesterol, apoE, apoE receptors, neuroanatomical factors, and aging in the Alzheimer disease brain.

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This article should be cited in the following way: Irizarry MC. Modulation of brain apolipoprotein E levels by the low-density lipoprotein receptor. Neurobiol. Lipids  Vol. 4, 2 (16 December 2005) Freely available at: http://neurobiologyoflipids.org/content/4/2/ ( Provide web address when citing this paper ) Please note: Because Neurobiology of Lipids is published online only, the articles should be cited with an article number rather than with traditional (printed) page numbers. Acrobat (.PDF) reprints of NoL article, however,  serve the algorithmic needs of tenure committees to count published print pages.

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