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Apolipoprotein E and Pathogenic Mechanisms in Human Diseases and Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (25 February 2019) | Viewed by 75501

Special Issue Editor

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Interests: Aging; Alzheimer's disease; Amyloid-β; Apolipoprotein E; Blood-brain barrier; Lipid metabolism; Neuroinflammation; Neurovascular diseases

Special Issue Information

Dear Colleagues, 

Apolipoprotein E (apoE) mediates the transport and delivery of cholesterol and other lipids through cell surface apoE receptors. While hepatocytes and macrophages are the major cell types synthesizing apoE in peripheral tissues, astrocytes, microglia, vascular mural cells and choroid plexus also produce apoE in the central nervous system. As apoE is likely involved in diverse aspects of physiological functions through the entire body, beyond lipid transport, the disturbance of the pathway possibly contributes to numerous diseases and disorders. In humans, there are three APOE genotypes (APOE2, APOE3 and APOE4). APOE genotypes influence blood lipid metabolism and cardiovascular disease risk. Furthermore, accumulating evidence has demonstrated that APOE genotypes are associated with risks and outcomes for various neurological diseases. In particular, since APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease, contributions of apoE to the disease pathogenesis have been extensively focused. Interestingly, APOE genotypes have been also shown to impact human longevity. Thus, this Special Issue of the International Journal of Molecular Sciences will focus on addressing apoE-related molecular mechanisms and APOE genotype-dependent effects in neurological and non-neurological diseases and disorders.

Dr. Takahisa Kanekiyo

Guest Editor

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Keywords

  • aging
  • Alzheimer's disease
  • cancer
  • cognitive function
  • lipid metabolism
  • metabolic syndrome
  • neurological diseases
  • immune system
  • vascular diseases

Published Papers (11 papers)

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Research

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12 pages, 2277 KiB  
Article
5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway
by Motoko Shinohara, Mitsuru Shinohara, Jing Zhao, Yuan Fu, Chia-Chen Liu, Takahisa Kanekiyo and Guojun Bu
Int. J. Mol. Sci. 2019, 20(6), 1488; https://doi.org/10.3390/ijms20061488 - 25 Mar 2019
Cited by 14 | Viewed by 3945
Abstract
Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low [...] Read more.
Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentrations significantly increased apoE secretion from immortalized astrocytes and primary astrocytes derived from apoE3 and apoE4-targeted replacement mice without generating cellular toxicity. Other 5-HT3 antagonists also had similar effects as OS, though their effects were milder and required higher concentrations. Antagonists for other 5-HT receptors did not increase apoE secretion. OS also increased mRNA and protein levels of the ATB-binding cassette protein A1 (ABCA1), which is involved in lipidation and secretion of apoE. Accordingly, OS increased high molecular weight apoE. Moreover, the liver X receptor (LXR) and ABCA1 antagonists blocked the OS-induced increase of apoE secretion, indicating that the LXR-ABCA1 pathway is involved in the OS-mediated facilitation of apoE secretion from astrocytes. The effects of OS on apoE and ABCA1 were also observed in human astrocytes derived from induced pluripotent stem cells (iPSC) carrying the APOE ε3/ε3 and APOE ε4/ε4 genotypes. Oral administration of OS at clinically-relevant doses affected apoE levels in the liver, though the effects in the brain were not observed. Collectively, though further studies are needed to probe its effects in vivo, OS could be a potential therapeutic drug for AD by modulating poE metabolism through the LXR-ABCA1 pathway. Full article
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13 pages, 1189 KiB  
Communication
The Opposite Effect of c-Jun Transcription Factor on Apolipoprotein E Gene Regulation in Hepatocytes and Macrophages
by Violeta G. Trusca, Elena V. Fuior, Dimitris Kardassis, Maya Simionescu and Anca V. Gafencu
Int. J. Mol. Sci. 2019, 20(6), 1471; https://doi.org/10.3390/ijms20061471 - 23 Mar 2019
Cited by 7 | Viewed by 4292
Abstract
Apolipoprotein E (apoE) is mainly secreted by hepatocytes and incorporated into most plasma lipoproteins. Macrophages, which accumulate cholesterol and are critical for the development of the atherosclerotic plaque, are also an important, albeit smaller, apoE source. Distal regulatory elements control cell-specific activity of [...] Read more.
Apolipoprotein E (apoE) is mainly secreted by hepatocytes and incorporated into most plasma lipoproteins. Macrophages, which accumulate cholesterol and are critical for the development of the atherosclerotic plaque, are also an important, albeit smaller, apoE source. Distal regulatory elements control cell-specific activity of the apoE promoter: multienhancers (ME.1/2) in macrophages and hepatic control regions (HCR-1/2) in hepatocytes. A member of AP-1 cell growth regulator, c-Jun regulates the transcription of various apolipoproteins and proinflammatory molecules implicated in atherosclerosis. We aimed to investigate the effect of c-Jun on apoE expression in macrophages versus hepatocytes and to reveal the underlying molecular mechanisms. Herein we show that c-Jun had an opposite, cell-specific effect on apoE expression: downregulation in macrophages but upregulation in hepatocytes. Transient transfections using ME.2 deletion mutants and DNA pull-down (DNAP) assays showed that the inhibitory effect of c-Jun on the apoE promoter in macrophages was mediated by a functional c-Jun binding site located at 301/311 on ME.2. In hepatocytes, c-Jun overexpression strongly increased apoE expression, and this effect was due to c-Jun binding at the canonical site located at −94/−84 on the apoE proximal promoter, identified by transient transfections using apoE deletion mutants, DNAP, and chromatin immunoprecipitation assays. Overall, the dual effect of c-Jun on apoE gene expression led to decreased cholesterol efflux in macrophages resident in the atherosclerotic plaque synergized with an increased level of systemic apoE secreted by the liver to exacerbate atherogenesis. Full article
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13 pages, 2733 KiB  
Article
Peach Kernel Oil Downregulates Expression of Tissue Factor and Reduces Atherosclerosis in ApoE knockout Mice
by Erwei Hao, Guofeng Pang, Zhengcai Du, Yu-Heng Lai, Jung-Ren Chen, Jinling Xie, Kai Zhou, Xiaotao Hou, Chung-Der Hsiao and Jiagang Deng
Int. J. Mol. Sci. 2019, 20(2), 405; https://doi.org/10.3390/ijms20020405 - 18 Jan 2019
Cited by 12 | Viewed by 4651
Abstract
Atherosclerosis is the pathological process in arteries due to the plaque formation that is responsible for several diseases like heart disease, stroke and peripheral arterial disease. In this study, we performed in vitro and in vivo assays to evaluate the potential anti-atherosclerosis activity [...] Read more.
Atherosclerosis is the pathological process in arteries due to the plaque formation that is responsible for several diseases like heart disease, stroke and peripheral arterial disease. In this study, we performed in vitro and in vivo assays to evaluate the potential anti-atherosclerosis activity of peach kernel oil. For the in vitro assay, we incubated human umbilical vein endothelial cells (HUVEC) with tumor necrosis factor-α (TNF-α) to induce tissue factors (TF, an essential mediator of hemostasis and trigger of thrombosis) elevation. We found that TNF-α-induced TF elevation was suppressed by peach kernel oil in a dose-dependent manner at both mRNA and protein levels. Peach kernel oil can significantly improve HUVEC viability, protect the endothelial cells, which achieved the goal of prevention of thrombotic diseases. For the in vivo assay, we investigated the effect and mechanism of peach kernel oil on preventing atherosclerotic lesion formation in ApoE knockout mice. Results show that peach kernel oil could reduce total cholesterol, triglyceride, low-density lipoprotein cholesterol levels, elevate the high-density lipoprotein cholesterol level in serum, and reduce the area of the aortic atherosclerotic lesions in high-fat diet fed ApoE knockout mice. Moreover, peach kernel oil treatment can significantly down regulate the expression of TF protein to inhibit the formation of atherosclerotic plaque. In conclusion, peach kernel oil may be a potential health food to prevent atherosclerosis in cardiovascular diseases. Full article
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13 pages, 1644 KiB  
Article
Transport of Apolipoprotein B-Containing Lipoproteins through Endothelial Cells Is Associated with Apolipoprotein E-Carrying HDL-Like Particle Formation
by Hong Yang, Ningya Zhang, Emmanuel U. Okoro and Zhongmao Guo
Int. J. Mol. Sci. 2018, 19(11), 3593; https://doi.org/10.3390/ijms19113593 - 14 Nov 2018
Cited by 10 | Viewed by 3017
Abstract
Passage of apolipoprotein B-containing lipoproteins (apoB-LPs), i.e., triglyceride-rich lipoproteins (TRLs), intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs), through the endothelial monolayer occurs in normal and atherosclerotic arteries. Among these lipoproteins, TRLs and IDLs are apoE-rich apoB-LPs (E/B-LPs). Recycling of TRL-associated apoE has been [...] Read more.
Passage of apolipoprotein B-containing lipoproteins (apoB-LPs), i.e., triglyceride-rich lipoproteins (TRLs), intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs), through the endothelial monolayer occurs in normal and atherosclerotic arteries. Among these lipoproteins, TRLs and IDLs are apoE-rich apoB-LPs (E/B-LPs). Recycling of TRL-associated apoE has been shown to form apoE-carrying high-density lipoprotein (HDL)-like (HDLE) particles in many types of cells. The current report studied the formation of HDLE particles by transcytosis of apoB-LPs through mouse aortic endothelial cells (MAECs). Our data indicated that passage of radiolabeled apoB-LPs, rich or poor in apoE, through the MAEC monolayer is inhibited by filipin and unlabeled competitor lipoproteins, suggesting that MAECs transport apoB-LPs via a caveolae-mediated pathway. The cholesterol and apoE in the cell-untreated E/B-LPs, TRLs, IDLs, and LDLs distributed primarily in the low-density (LD) fractions (d ≤ 1.063). A substantial portion of the cholesterol and apoE that passed through the MAEC monolayer was allotted into the high-density (HD) (d > 1.063) fractions. In contrast, apoB was detectable only in the LD fractions before or after apoB-LPs were incubated with the MAEC monolayer, suggesting that apoB-LPs pass through the MAEC monolayer in the forms of apoB-containing LD particles and apoE-containing HD particles. Full article
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18 pages, 4213 KiB  
Article
Administration of Downstream ApoE Attenuates the Adverse Effect of Brain ABCA1 Deficiency on Stroke
by Xiaohui Wang, Rongwen Li, Alex Zacharek, Julie Landschoot-Ward, Fengjie Wang, Kuan-Han Hank Wu, Michael Chopp, Jieli Chen and Xu Cui
Int. J. Mol. Sci. 2018, 19(11), 3368; https://doi.org/10.3390/ijms19113368 - 28 Oct 2018
Cited by 13 | Viewed by 4046
Abstract
The ATP-binding cassette transporter member A1 (ABCA1) and apolipoprotein E (ApoE) are major cholesterol transporters that play important roles in cholesterol homeostasis in the brain. Previous research demonstrated that specific deletion of brain-ABCA1 (ABCA1−B/−B) reduced brain grey matter (GM) and white [...] Read more.
The ATP-binding cassette transporter member A1 (ABCA1) and apolipoprotein E (ApoE) are major cholesterol transporters that play important roles in cholesterol homeostasis in the brain. Previous research demonstrated that specific deletion of brain-ABCA1 (ABCA1−B/−B) reduced brain grey matter (GM) and white matter (WM) density in the ischemic brain and decreased functional outcomes after stroke. However, the downstream molecular mechanism underlying brain ABCA1-deficiency-induced deficits after stroke is not fully understood. Adult male ABCA1−B/−B and ABCA1-floxed control mice were subjected to distal middle-cerebral artery occlusion and were intraventricularly infused with artificial mouse cerebrospinal fluid as vehicle control or recombinant human ApoE2 into the ischemic brain starting 24 h after stroke for 14 days. The ApoE/apolipoprotein E receptor 2 (ApoER2)/high-density lipoprotein (HDL) levels and GM/WM remodeling and functional outcome were measured. Although ApoE2 increased brain ApoE/HDL levels and GM/WM density, negligible functional improvement was observed in ABCA1-floxed-stroke mice. ApoE2-administered ABCA1−B/−B stroke mice exhibited elevated levels of brain ApoE/ApoER2/HDL, increased GM/WM density, and neurogenesis in both the ischemic ipsilateral and contralateral brain, as well as improved neurological function compared with the vehicle-control ABCA1−B/−B stroke mice 14 days after stroke. Ischemic lesion volume was not significantly different between the two groups. In vitro supplementation of ApoE2 into primary cortical neurons and primary oligodendrocyte-progenitor cells (OPCs) significantly increased ApoER2 expression and enhanced cholesterol uptake. ApoE2 promoted neurite outgrowth after oxygen-glucose deprivation and axonal outgrowth of neurons, and increased proliferation/survival of OPCs derived from ABCA1−B/−B mice. Our data indicate that administration of ApoE2 minimizes the adverse effects of ABCA1 deficiency after stroke, at least partially by promoting cholesterol traffic/redistribution and GM/WM remodeling via increasing the ApoE/HDL/ApoER2 signaling pathway. Full article
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Review

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13 pages, 1749 KiB  
Review
The Role of ApoE in HCV Infection and Comorbidity
by Yue Gong and Wei Cun
Int. J. Mol. Sci. 2019, 20(8), 2037; https://doi.org/10.3390/ijms20082037 - 25 Apr 2019
Cited by 12 | Viewed by 4402
Abstract
Hepatitis C virus (HCV) is an RNA virus that can efficiently establish chronic infection in humans. The overlap between the HCV replication cycle and lipid metabolism is considered to be one of the primary means by which HCV efficiently develops chronic infections. In [...] Read more.
Hepatitis C virus (HCV) is an RNA virus that can efficiently establish chronic infection in humans. The overlap between the HCV replication cycle and lipid metabolism is considered to be one of the primary means by which HCV efficiently develops chronic infections. In the blood, HCV is complex with lipoproteins to form heterogeneous lipo-viro-particles (LVPs). Furthermore, apolipoprotein E (ApoE), which binds to receptors during lipoprotein transport and regulates lipid metabolism, is localized on the surface of LVPs. ApoE not only participate in the attachment and entry of HCV on the cell surface but also the assembly and release of HCV viral particles from cells. Moreover, in the blood, ApoE can also alter the infectivity of HCV and be used by HCV to escape recognition by the host immune system. In addition, because ApoE can also affect the antioxidant and immunomodulatory/anti-inflammatory properties of the host organism, the long-term binding and utilization of host ApoE during chronic HCV infection not only leads to liver lipid metabolic disorders but may also lead to increased morbidity and mortality associated with systemic comorbidities. Full article
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31 pages, 1369 KiB  
Review
The Contribution of Genetic Factors to Cognitive Impairment and Dementia: Apolipoprotein E Gene, Gene Interactions, and Polygenic Risk
by Jialing Fan, Wuhai Tao, Xin Li, He Li, Junying Zhang, Dongfeng Wei, Yaojing Chen and Zhanjun Zhang
Int. J. Mol. Sci. 2019, 20(5), 1177; https://doi.org/10.3390/ijms20051177 - 07 Mar 2019
Cited by 41 | Viewed by 7050
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Although it has been studied for years, the pathogenesis of AD is still controversial. Genetic factors may play an important role in pathogenesis, with the apolipoprotein E (APOE) gene among the greatest risk [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Although it has been studied for years, the pathogenesis of AD is still controversial. Genetic factors may play an important role in pathogenesis, with the apolipoprotein E (APOE) gene among the greatest risk factors for AD. In this review, we focus on the influence of genetic factors, including the APOE gene, the interaction between APOE and other genes, and the polygenic risk factors for cognitive function and dementia. The presence of the APOE ε4 allele is associated with increased AD risk and reduced age of AD onset. Accelerated cognitive decline and abnormal internal environment, structure, and function of the brain were also found in ε4 carriers. The effect of the APOE promoter on cognition and the brain was confirmed by some studies, but further investigation is still needed. We also describe the effects of the associations between APOE and other genetic risk factors on cognition and the brain that exhibit a complex gene–gene interaction, and we consider the importance of using a polygenic risk score to investigate the association between genetic variance and phenotype. Full article
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20 pages, 1480 KiB  
Review
The Role of APOE and TREM2 in Alzheimer′s Disease—Current Understanding and Perspectives
by Cody M. Wolfe, Nicholas F. Fitz, Kyong Nyon Nam, Iliya Lefterov and Radosveta Koldamova
Int. J. Mol. Sci. 2019, 20(1), 81; https://doi.org/10.3390/ijms20010081 - 26 Dec 2018
Cited by 118 | Viewed by 17776
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. The extracellular deposits of Amyloid beta (Aβ) in the brain—called amyloid plaques, and neurofibrillary tangles—intracellular tau aggregates, are morphological hallmarks of the disease. The risk for AD is a complicated interplay between aging, [...] Read more.
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. The extracellular deposits of Amyloid beta (Aβ) in the brain—called amyloid plaques, and neurofibrillary tangles—intracellular tau aggregates, are morphological hallmarks of the disease. The risk for AD is a complicated interplay between aging, genetic risk factors, and environmental influences. One of the Apolipoprotein E (APOE) alleles—APOEε4, is the major genetic risk factor for late-onset AD (LOAD). APOE is the primary cholesterol carrier in the brain, and plays an essential role in lipid trafficking, cholesterol homeostasis, and synaptic stability. Recent genome-wide association studies (GWAS) have identified other candidate LOAD risk loci, as well. One of those is the triggering receptor expressed on myeloid cells 2 (TREM2), which, in the brain, is expressed primarily by microglia. While the function of TREM2 is not fully understood, it promotes microglia survival, proliferation, and phagocytosis, making it important for cell viability and normal immune functions in the brain. Emerging evidence from protein binding assays suggests that APOE binds to TREM2 and APOE-containing lipoproteins in the brain as well as periphery, and are putative ligands for TREM2, thus raising the possibility of an APOE-TREM2 interaction modulating different aspects of AD pathology, potentially in an isoform-specific manner. This review is focusing on the interplay between APOE isoforms and TREM2 in association with AD pathology. Full article
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12 pages, 421 KiB  
Review
The Synergistic Effects of APOE Genotype and Obesity on Alzheimer’s Disease Risk
by Nahdia S. Jones and G. William Rebeck
Int. J. Mol. Sci. 2019, 20(1), 63; https://doi.org/10.3390/ijms20010063 - 24 Dec 2018
Cited by 41 | Viewed by 7693
Abstract
The APOE gene has three common alleles—E2, E3, and E4, with APOE4 being the strongest genetic risk factor for developing Alzheimer’s Disease (AD). Obesity is a global epidemic and contributes to multiple metabolic problems. Obesity is also a risk factor for cognitive decline. [...] Read more.
The APOE gene has three common alleles—E2, E3, and E4, with APOE4 being the strongest genetic risk factor for developing Alzheimer’s Disease (AD). Obesity is a global epidemic and contributes to multiple metabolic problems. Obesity is also a risk factor for cognitive decline. Here, we review the effects of APOE4 and obesity on cognition and AD development, independently and together. We describe studies that have associated APOE4 with cognitive deficits and AD, as well as studies that have associated obesity to cognitive deficits and AD. We then describe studies that have examined the effects of obesity and APOE genotypes together, with a focus on APOE4 and high fat diets. Both human studies and rodent models have contributed to understanding the effects of obesity on the different APOE genotypes, and we outline possible underlying mechanisms associated with these effects. Data across approaches support a model in which APOE4 and obesity combine for greater detrimental effects on metabolism and cognition, in ways that are influenced by both age and sex. Full article
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10 pages, 1030 KiB  
Review
Apoprotein E and Reverse Cholesterol Transport
by Godfrey S. Getz and Catherine A. Reardon
Int. J. Mol. Sci. 2018, 19(11), 3479; https://doi.org/10.3390/ijms19113479 - 06 Nov 2018
Cited by 57 | Viewed by 8313
Abstract
Apoprotein E (apoE) is a multifunctional protein. Its best-characterized function is as a ligand for low-density lipoprotein (LDL) receptor family members to mediate the clearance of apoB-containing atherogenic lipoproteins. Among its other functions, apoE is involved in cholesterol efflux, especially from cholesterol-loaded macrophage [...] Read more.
Apoprotein E (apoE) is a multifunctional protein. Its best-characterized function is as a ligand for low-density lipoprotein (LDL) receptor family members to mediate the clearance of apoB-containing atherogenic lipoproteins. Among its other functions, apoE is involved in cholesterol efflux, especially from cholesterol-loaded macrophage foam cells and other atherosclerosis-relevant cells, and in reverse cholesterol transport. Reverse cholesterol transport is a mechanism by which excess cellular cholesterol is transported via lipoproteins in the plasma to the liver where it can be excreted from the body in the feces. This process is thought to have a role in the attenuation of atherosclerosis. This review summarizes studies on the role of apoE in cellular cholesterol efflux and reverse cholesterol transport and discusses the identification of apoE mimetic peptides that may promote these pathways. Full article
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22 pages, 2349 KiB  
Review
The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor
by Paula Dlugosz and Johannes Nimpf
Int. J. Mol. Sci. 2018, 19(10), 3090; https://doi.org/10.3390/ijms19103090 - 09 Oct 2018
Cited by 46 | Viewed by 9531
Abstract
Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal [...] Read more.
Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal transduction receptors. The best characterized signaling pathway in which ApoER2 and VLDL receptor (VLDLR) are involved is the Reelin pathway. This pathway plays a pivotal role in the development of laminated structures of the brain and in synaptic plasticity of the adult brain. Since Reelin and apolipoprotein E, are ligands of ApoER2 and VLDLR, these receptors are of interest with respect to Alzheimer’s disease. We will focus this review on the complex structure of ApoER2 and VLDLR and a recently characterized ligand, namely clusterin. Full article
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