The DOI matches its Crossref record; 87 of the 88 references it cites were found in a registry or an index.
Apolipoprotein E structure: insights into function
Abstract
Human apolipoprotein E (apoE) is a member of the family of soluble apolipoproteins. Through its interaction with members of the low-density lipoprotein receptor family, apoE has a key role in lipid transport both in the plasma and in the central nervous system. Its three common structural isoforms differentially affect the risk of developing atherosclerosis and neurodegenerative disorders, including Alzheimer's disease. Because the function of apoE is dictated by its structure, understanding the structural properties of apoE and its isoforms is required both to determine its role in disease and for the development of therapeutic strategies.
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In the citing paper
“Several biophysical studies have shown that apoE displays low thermodynamic stability and significant conformational plasticity, and allelic differences as well as single point mutations have been shown to affect protein conformation and to hinder physiological function”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [13]
In the citing paper
“Several biophysical studies have shown that apoE displays low thermodynamic stability and significant conformational plasticity, and allelic differences as well as single point mutations have been shown to affect protein conformation and to hinder physiological function”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [13]
In the citing paper
“Inter-domain interactions within apoE have been hypothesized to underlie key conformational changes related to apoE function [44], [45].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [44]
In the citing paper
“Several studies have suggested that the structural and biophysical properties of apoE can dictate the function of the protein and have provided insight into the mechanisms by which apoE is involved in cardiovascular and neurological diseases [42], [43], [44], [45], [46], [47], [48], [49].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [44]
In the citing paper
“of the second unfolding transition of apoE3 variant (Table 3) that corresponds to the unfolding of the N-terminal domain where the K146E mutation is located [13], [44], [65].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [44]
In the citing paper
“Apo E4 isoform is associated with elevated total and LDL-cholesterol levels, due to the higher affinity of apo E4 for VLDL and LDL”
From Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the APOE p.Leu167del Mutation (2013) · cites this paper as Hatters DM et al. 2006
In the citing paper
“Mutated ApoE2 (Arg158Cys) exhibits only 2% affinity to LDL receptor compared to the wide type ApoE3 isoform [13]”
From A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation (2024) · cites this paper as [13]
In the citing paper
“Biophysical and computational analyses suggest that unfolding of the N-terminal domain constitutes a necessary conformational change for lipid binding and apoE function (19).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [19]
In the citing paper
“ApoE variants with lower thermodynamic stability and changes in conformational plasticity have been shown to have altered interdomain interactions and defective physiological functions (19, 24 -28).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [19]
In the citing paper
“First, apoE4 preferentially forms a “molten globule state” that ultimately reduces the in vitro stability of apoE4 relative to the other isoforms.”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Hatters et al., 2006
In the citing paper
“Second, apoE4 forms a unique salt bridge interaction between Arg-61 in the N terminal and Glu-255 in the carboxy-terminal domain.”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Hatters et al., 2006
In the citing paper
“ApoE contains two independently folded functional domains; these are a 22-kDa N-terminal domain (residues 1–191) and a 10-kDa C-terminal domain (residues 216–299) linked by a hinge region (18, 19).”
From Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study (2008) · cites this paper as [19]
In the citing paper
“This domain interaction mediated by a salt bridge formation between Arg-61 and Glu-255 is unique to apoE4 (Fig. 1) [15].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [15]
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Lee, Y., Kockx, M., Raftery, M. J., Jessup, W., Griffith, R., & Kritharides, L. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m900430-mcp200 · Cited by 74
“Structural studies on apoE have provided important insights into its biological properties (13).”
BackgroundHubin, E., Verghese, P. B., van Nuland, N., & Broersen, K. (2019) · FEBS Letters · doi:10.1002/1873-3468.13428 · Cited by 73
Melatonin: A potential nighttime guardian against Alzheimer’s
Zhang, Z., Xue, P., Bendlin, B. B., Zetterberg, H., Felice, F. G. D., Tan, X. W., & Benedict, C. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02691-6 · Cited by 76
Studying the Protein Corona on Nanoparticles by FCS
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Lipids in Amyloid-β Processing, Aggregation, and Toxicity
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Human apolipoprotein E peptides inhibit hepatitis C virus entry by blocking virus binding
Liu, S., McCormick, K. D., Zhao, W., Zhao, T., Fan, D., & Wang, T. (2012) · Hepatology · doi:10.1002/hep.25665 · Cited by 73
“In the lipid-free state, apoE contains two independently folded structural domains: the N-terminal four-helixbundle structure that harbors the LDLR binding region (residues 136-150), and the C-terminal domain containing the major lipid-binding region (residues 245-266).(18) Based on this knowledge, we designed a human…”
Zhang, Z., Xin, X., Liu, C., Liu, Y., Duan, H., Qi, L., Zhang, Y., Zhao, H., Chen, L., Jin, M., et al. (2021) · Journal of Nanobiotechnology · doi:10.1186/s12951-021-01097-8 · Cited by 70
“Second, the lipid-binding site involves residues 244–272 of the C-terminal domain of ApoE and has a high percentage of α-helices [21, 22].”
BackgroundThe Association−Dissociation Behavior of the ApoE Proteins: Kinetic and Equilibrium Studies
Garai, K., & Frieden, C. (2010) · Biochemistry · doi:10.1021/bi101407m · Cited by 67
“The complete structure of wildtype ApoE is unknown, but the ApoE monomer consists of two domains, an N-terminal domain (residues 1-191) and a C-terminal domain (residues 221-299) (5, 6) with the arginine to cysteine changes occurring in the N-terminal domain.”
Tan, L. X., Germer, C. J., Cunza, N. L., & Lakkaraju, A. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101781 · Cited by 71
Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers
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Recent advances in biosensors for neurodegenerative disease detection
Ganesh, H. V. S., Chow, A. M., & Kerman, K. (2016) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2016.02.012 · Cited by 69
The helix bundle: A reversible lipid binding motif
Narayanaswami, V., Kiss, R. S., & Weers, P. M. M. (2009) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2009.09.009 · Cited by 69
“In contrast to insect apoLp-III, mammalian apoE is 299 residues long, with the structure organized as two domains: an N-terminal (NT) and a C-terminal (CT) domain, comprising residues 1–191 and 201–299, respectively (Weisgraber, 1994; Hatters et al., 2006).”
BackgroundLa Cunza, N., Tan, L. X., Thamban, T., Germer, C. J., Rathnasamy, G., Toops, K. A., & Lakkaraju, A. (2021) · JCI Insight · doi:10.1172/jci.insight.142254 · Cited by 65
“6 function, including oligomer formation, and binding to lipids and receptors (23-27).”
BackgroundNanodisks: hydrophobic drug delivery vehicles
Ryan, R. O. (2008) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.5.3.343 · Cited by 65
“Reconstituted high density lipoprotein (rHDL) has been employed in studies of cholesterol esterification [3] , cellular cholesterol efflux as part of the reverse cholesterol transport pathway [4] , HDL maturation [5] and structure–function studies of apolipoprotein–lipid complexes [6-8] .”
BackgroundGenotype–Phenotype Associations: Modulation by Diet and Obesity
Ordovás, J. M. (2008) · Obesity · doi:10.1038/oby.2008.515 · Cited by 65
Molecular Mechanism of Apolipoprotein E Binding to Lipoprotein Particles
Nguyen, D., Dhanasekaran, P., Phillips, M. C., & Lund‐Katz, S. (2009) · Biochemistry · doi:10.1021/bi9000694 · Cited by 66
“the interaction between the N- and C-terminal domains (3, 6).”
InfluentialHCV Pit Stop at the Lipid Droplet: Refuel Lipids and Put on a Lipoprotein Coat before Exit
Vièyres, G., & Pietschmann, T. (2019) · Cells · doi:10.3390/cells8030233 · Cited by 64
“The reversible change between lipoprotein-bound and lipid-free states is accompanied by a dramatic structural reorganization of the apolipoprotein, as illustrated for ApoE [126,127].”
BackgroundMechanisms behind the atherothrombotic effects of acrolein, a review
Zirak, M. R., Mehri, S., Karimani, A., Zeinali, M., Hayes, A. W., & Karimi, G. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2019.04.034 · Cited by 65
Human apolipoprotein E promotes hepatitis B virus infection and production
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Quantifying Diet for Nutrigenomic Studies
Tucker, K. L., Smith, C. E., Lai, C., & Ordovás, J. M. (2013) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-072610-145203 · Cited by 65
“As an example, one of the earliest genetic polymorphisms to gain widespread acknowledgment as a modulator of disease risk is apolipoprotein E (APOE), including risk of cardiovascular disease (CVD), cognitive decline and neurological disorders (19, 22, 46, 61, 64, 71), cancer (117), osteoporosis (2, 23), and earlier mo…”
BackgroundSpns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage
He, M., Kuk, A. C. Y., Ding, M., Chin, C. F., Galam, D. L. A., Nah, J. M., Tan, B. C., Yeo, H. L., Chua, G. L., Benke, P. I., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2210353119 · Cited by 62
Apolipophorins and insects immune response
Zdybicka‐Barabas, A., & Cytryńska, M. (2013) · Invertebrate survival journal · Cited by 60
Watson, C. M., Dammer, E. B., Ping, L., Duong, D. M., Modeste, E. S., Carter, E. K., Johnson, E. C. B., Levey, A. I., Lah, J. J., Roberts, B. R., et al. (2023) · Scientific Data · doi:10.1038/s41597-023-02158-3 · Cited by 59
Proteome analysis of rat serum proteins adsorbed onto synthetic octacalcium phosphate crystals
Kaneko, H., Kamiie, J., Kawakami, H., Anada, T., Honda, Y., Shiraishi, N., Kamakura, S., Terasaki, T., Shimauchi, H., & Suzuki, O. (2011) · Analytical Biochemistry · doi:10.1016/j.ab.2011.07.022 · Cited by 59
“Apo E contains 299 residues and amphilipathic a-helical lipidbinding domains [62].”
BackgroundPocivavsek, A., MIKHAILENKO, I. A., Strickland, D. K., & Rebeck, G. W. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.06.010 · Cited by 63
“This altered structure reduces the stability of apoE (Hatters et al., 2006), resulting in preferential degradation of apoE4 by glial cells (Riddell et al.”
APOE genotype is associated with left-handedness and visuospatial skills in children
Bloss, C. S., Delis, D. C., Salmon, D. P., & Bondi, M. W. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.05.021 · Cited by 58
“Another possibility is that APOE itself could play a role with respect to the development of this phenotype given known differences in structure between the different APOE isoforms (Hatters et al., 2006), which have been shown to produce different functional consequences that may impact neurodevelopment (Weisgraber et…”
BackgroundGarai, K., Baban, B., & Frieden, C. (2011) · Biochemistry · doi:10.1021/bi1020106 · Cited by 57
Interaction with Amyloid β Peptide Compromises the Lipid Binding Function of Apolipoprotein E
Tamamizu‐Kato, S., Cohen, J. K., Drake, C. B., Kosaraju, M. G., Drury, J., & Narayanaswami, V. (2008) · Biochemistry · doi:10.1021/bi702097s · Cited by 56
Yamauchi, Y., Deguchi, N., Takagi, C., Tanaka, M., Dhanasekaran, P., Nakano, M., Handa, T., Phillips, M. C., Lund-Katz, S., & Saito, H. (2008) · Biochemistry · doi:10.1021/bi8003999 · Cited by 53
“ApoE contains two independently folded functional domains; these are a 22-kDa N-terminal domain (residues 1–191) and a 10-kDa C-terminal domain (residues 216–299) linked by a hinge region (18,19).”
BackgroundApolipoprotein E•dipalmitoylphosphatidylcholine particles are ellipsoidal in solution
Peters-Libeu, C. A., Newhouse, Y. M., Hall, S. C., Witkowska, H. E., & Weisgraber, K. H. (2007) · Journal of Lipid Research · doi:10.1194/jlr.m600545-jlr200 · Cited by 54
“In both proteins, the four-helix bundle must undergo a conformational change when the protein binds to lipid before it achieves its biologically active conformation (7, 10, 11).”
BackgroundSelf-citationAkita, H., Tamaru, M., Kajimoto, K., Sato, Y., Hatakeyama, H., Harashima, H., & Nakatani, T. (2014) · International Journal of Nanomedicine · doi:10.2147/ijn.s65402 · Cited by 55
“ApoE is a member of the soluble apolipoprotein family that plays a key role in the cell-to-cell delivery of lipoproteins via the low-density lipoprotein (LDL) receptor family or heparin sulfate proteoglycan.(12) Our recent findings demonstrated that preliminary incubation of YSK-MEND with recombinant ApoE stimulated c…”
In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS
Wildsmith, K. R., Basak, J. M., Patterson, B. W., Pyatkivskyy, Y., Kim, J., Yarasheski, K. E., Wang, J. X., Mawuenyega, K. G., Jiang, H., Parsadanian, M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038013 · Cited by 54
“The prevalence of e2, e3, and e4 alleles in European Americans is 7%, 78%, and 15%, respectively [2].”
BackgroundReceptor-associated Protein Interacts with Amyloid-β Peptide and Promotes Its Cellular Uptake
Kanekiyo, T., & Bu, G. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.015032 · Cited by 44
ApoE Induces Serum Paraoxonase PON1 Activity and Stability Similar to ApoA-I
Gaidukov, L., I, V. R., Yacobson, S., Rosenblat, M., Aviram, M., & Tawfik, D. S. (2009) · Biochemistry · doi:10.1021/bi9013227 · Cited by 54
An altered pattern of circulating apolipoprotein E3 isoforms is implicated in preeclampsia
Atkinson, K. R., Blumenstein, M., Black, M. A., Wu, S., Kasabov, N. K., Taylor, R. S., Cooper, G. J. S., & North, R. A. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m800296-jlr200 · Cited by 53
Introducing Human APOE into A β Transgenic Mouse Models
Tai, L. M., Youmans, K. L., Jungbauer, L., Yu, C., & LaDu, M. J. (2011) · International Journal of Alzheimer’s Disease · doi:10.4061/2011/810981 · Cited by 52
“These models include but are not limited to: PDAPP (APPV717F), Tg2576 (APPK670N,M671L), J9 (PS1M146V,L286V, APPV717F), as well as 5xFAD (APPK670N,M671L,I716V,V717I, PS1M146V,L286V) (reviewed in [2]).”
BackgroundInfluentialBlanchette, C., Law, R., Benner, W. H., Pesavento, J. B., Cappuccio, J. A., Walsworth, V. L., Kuhn, E. A., Corzett, M., Chromy, B. A., Segelke, B. W., et al. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m700586-jlr200 · Cited by 53
High-density lipoproteins (HDL): Novel function and therapeutic applications
Darabi, M., & Kontush, A. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2021.159058 · Cited by 52
Haley, G. E., Kohama, S. G., Urbanski, H. F., & Raber, J. (2010) · AGE · doi:10.1007/s11357-010-9137-9 · Cited by 51
“One potential reason for the lack of behavioral deficits as observed with AD is that the apoE ε4 allele in the rhesus macaque does not have arginine at position 61, which is responsible for the domain interaction observed with human apoE ε4 (Morelli et al. 1996; Hatters et al. 2006).”
BackgroundA differential association of Apolipoprotein E isoforms with the amyloid‐β oligomer in solution
Petrlová, J., Hong, H., Bricarello, D. A., Ghimire, H., Lorigan, G. A., Jin, L., & Voss, J. C. (2010) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22891 · Cited by 51
“ApoE (30 lM) containing a spin label at position 264 was combined with HDL or VLDL (850 mg/dL), and then oligomeric Ab(1-40) (100 lM) was added to the mixture and incubated for 1 h at 378C, followed by EPR spectroscopy.”
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Dallinga‐Thie, G. M., Dullaart, R. P. F., & van Tol, A. (2007) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3280e12685 · Cited by 50
In Vivo and In Vitro Effects of an Apolipoprotein E Mimetic Peptide on Amyloid-β Pathology
Handattu, S. P., Monroe, C. E., Nayyar, G., Palgunachari, M. N., Kadish, I., van Groen, T., Anantharamaiah, G. M., & Garber, D. W. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-122377 · Cited by 50
TIP47, a Lipid Cargo Protein Involved in Macrophage Triglyceride Metabolism
Buers, I., Robenek, H., Stefan Lorkowski, A., Nitschke, Y., Severs, N. J., & Hofnagel, O. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.182675 · Cited by 49
Zhang, M., Gu, W., Qiao, S.-B., Zhu, E., Zhao, Q., & Lv, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095463 · Cited by 49
“The three corresponding encoded isoforms: E2, E3 and E4 have different functional properties [10].”
BackgroundPinhel, M. A. S., Nakazone, M. A., Cação, J. D. C., Piteri, R. C. D. O., Dantas, R. T., de Godoy, M. F., de Godoy, M. R. P., Tognola, W. A., Conforti-Froes, N. D. T., & Souza, D. R. S. (2008) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2008.102 · Cited by 48
“degeneration/regeneration processes of nervous tissues (7).”
Chong, B. M., Russell, T. D., Schaack, J. B., Orlicky, D. J., Reigan, P., Ladinsky, M. S., & McManaman, J. L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.217091 · Cited by 48
Tamaru, M., Akita, H., Kajimoto, K., Sato, Y., Hatakeyama, H., & Harashima, H. (2014) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2014.02.016 · Cited by 48
The potential applications of Apolipoprotein E in personalized medicine
Villeneuve, S., Brisson, D., Marchant, N. L., & Gaudet, D. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00154 · Cited by 50
“In the brain, ApoE is produced by astrocytes and, to a minor extent, by microglia (Pitas et al., 1987; Grehan et al., 2001), and can also be produced by neurons in response to neuronal injury or stress (Mahley and Huang, 2012a).”
BackgroundEarly- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?
Valdez-Gaxiola, C. A., Rosales-Leycegui, F., Gaxiola-Rubio, A., Moreno-Ortíz, J. M., & Figuera, L. E. (2024) · Diseases · doi:10.3390/diseases12060110 · Cited by 55
“However, the presence of the APOE ε 4 allele correlates with pronounced disruption in white matter integrity (Figure 3 summarize the pathological mechanism) [11,57].”
BackgroundDifferential effects of apolipoprotein E3 and E4 on markers of oxidative status in macrophages
Jofre‐Monseny, L., de Pascual‐Teresa, S., Plonka, E., Huebbe, P., Boesch, C., Minihane, A. M., & Rimbach, G. H. (2007) · British Journal Of Nutrition · doi:10.1017/s0007114507669219 · Cited by 47
“Due to the exchange of a Cys by an Arg at position 112 in apoE4, a domain interaction arises which leads to a less stable protein, with folding intermediates which are more rapidly degraded and which influence the affinity of apoE for different lipoproteins (Hatters et al. 2006).”
BackgroundWintjens, R., Bozon, D., Belabbas, K., MBou, F., Girardet, J.-P., Tounian, P., Jolly, M., Boccara, F., Cohen, A., Karsenty, A., et al. (2016) · Journal of Lipid Research · doi:10.1194/jlr.p055699 · Cited by 47
From beta amyloid to altered proteostasis in Alzheimer’s disease
Bruni, A. C., Bernardi, L., & Gabelli, C. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101126 · Cited by 47
Cholesterol Regulates Exosome Release in Cultured Astrocytes
Abdullah, M. S., Nakamura, T., Ferdous, T., Gao, Y., Chen, Y., Zou, K., & Michikawa, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.722581 · Cited by 38
Giannisis, A., Al-Grety, A., Carlsson, H., Patra, K., Twohig, D., Sando, S. B., Lauridsen, C., Berge, G., Grøntvedt, G. R., Bråthen, G., et al. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01058-9 · Cited by 46
Implications of apolipoprotein E genotype on inflammation and vitamin E status
Huebbe, P., Lodge, J. K., & Rimbach, G. (2010) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200900398 · Cited by 43
“2 0 0 5 [1 9 ]”
BackgroundChen, Y., Chou, C., Chang, T., Ting, H., Dembélé, J., Chu, Y.-T., Liu, T., Changou, C. A., Liu, C.-W., & Chen, C.-T. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.931584 · Cited by 47
“ApoE, a lipids transporter in the plasma and the central nervous system (Hatters et al., 2006), can promote neurite growth and act as a ligand of lipoproteins receptors for targeting delivery to the brain (Beffert et al.”
BackgroundA multi‐hit hypothesis for an APOE4 ‐dependent pathophysiological state
Steele, O. G., Stuart, A. C., Minkley, L., Shaw, K., Bonnar, O., Anderle, S., Penn, A. C., Rusted, J., Serpell, L., Hall, C., et al. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15685 · Cited by 44
Jiang, Y. Q., & Brody, D. L. (2012) · Journal of Neurotrauma · doi:10.1089/neu.2012.2362 · Cited by 44
“In response to injury, apoE may exert neuroprotective effects via multiple mechanisms including antioxidant, antiinflammatory, anti-excitotoxic, and neurotrophic mechanisms (Hatters et al., 2006; Verghese et al., 2011).”
Function and Comorbidities of Apolipoprotein E in Alzheimer′s Disease
Leduc, V., Domenger, D., Beaumont, L. D., Lalonde, D., Jasmin, S. B., & Poirier, J. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/974361 · Cited by 46
“Yet, molten-globulelike conformations are more prone to proteolysis, more vulnerable to degradation pathways and have been implicated in several diseases [44, 64].”
InfluentialLin, Z., Zhou, B., Wu, W., Xing, L., & Zhao, Q. S. (2013) · Faraday Discussions · doi:10.1039/c3fd00068k · Cited by 44
Links between copper and cholesterol in Alzheimer's disease
Hung, Y. H., Bush, A. I., & Fontaine, S. L. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00111 · Cited by 44
“However, this may not be feasible based on apoE structural studies [reviewed in Hatters et al. (2006)], which suggest that these cysteine residues are positioned in an opposing orientation.”
BackgroundHaapasalo, K., van Kessel, K. P. M., Nissilä, E., Metso, J., Johansson, T., Miettinen, S., Varjosalo, M. T., Kirveskari, J., Kuusela, P., Chroni, A., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.669226 · Cited by 43
“As a result, apoE2 is associated with type III hyperlipoproteinemia (33), and apoE4 is associated with, for example, Alzheimer disease (34).”
BackgroundThe New Frontiers in Neurodegenerative Diseases Treatment: Liposomal-Based Strategies
Cascione, M., Matteis, V. D., Leporatti, S., & Rinaldi, R. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.566767 · Cited by 44
MacKay, D., Eck, P., Gebauer, S. K., Baer, D. J., & Jones, P. J. H. (2015) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.115.109231 · Cited by 42
Lipid-Binding Proteins in Brain Health and Disease
Corraliza-Gómez, M., Sánchez, D., & Ganfornina, M. D. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01152 · Cited by 43
Apolipoprotein E Effects on Mammalian Ovarian Steroidogenesis and Human Fertility
Oriá, R. B., de Almeida, J. Z., Moreira, C. N., Guerrant, R. L., & Figueiredo, J. R. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.06.003 · Cited by 45
Apolipoprotein E Mimetics and Cholesterol-Lowering Properties
Sharifov, O. F., Nayyar, G., Garber, D. W., Handattu, S. P., Mishra, V., Goldberg, D., Anantharamaiah, G. M., & Gupta, H. (2011) · American Journal of Cardiovascular Drugs · doi:10.2165/11594190-000000000-00000 · Cited by 41
Possible function of VIPP1 in maintaining chloroplast membranes
Zhang, L., & Sakamoto, W. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.02.013 · Cited by 41
Apolipoprotein E Gene Polymorphism in the Mongolian Population
Svobodová, H., Kučera, F., Štulc, T., Vrablı́k, M., Amartuvshin, B., Altannavch, T., & Češka, R. (2007) · Folia Biologica · doi:10.14712/fb2007053040138 · Cited by 40
“The presence of three alleles leads to the formation of six different phenotypes: E2/2, E2/3, E2/4, E3/3, E3/4, E4/4 (Utermann et al., 1977; Hatters et al., 2006 ).”
InfluentialThe Role of Apolipoprotein E Isoforms in Alzheimer’s Disease
Roda, A. R., Montoliu‐Gaya, L., & Villegas, S. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-180740 · Cited by 41
“In the periphery, ApoE3 and ApoE2 display preference for HDL binding, whereas ApoE4 is mainly associated with VLDL and LDL [90].”
Multi-functional role of apolipoprotein E in neurodegenerative diseases
Islam, S., Noorani, A. A., Sun, Y., Michikawa, M., & Zou, K. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1535280 · Cited by 43
Type III Hyperlipoproteinemia: Still Worth Considering?
Blum, C. B. (2016) · Progress in Cardiovascular Diseases · doi:10.1016/j.pcad.2016.07.007 · Cited by 39
High‐affinity multivalent interactions between apolipoprotein E and the oligomers of amyloid‐β
Ghosh, S., Sil, T. B., Dolai, S., & Garai, K. (2019) · FEBS Journal · doi:10.1111/febs.14988 · Cited by 40
Repurposing of synaptonemal complex proteins for kinetochores in Kinetoplastida
Tromer, E. C., Wemyss, T. A., Ludzia, P., Waller, R. F., & Akiyoshi, B. (2021) · Open Biology · doi:10.1098/rsob.210049 · Cited by 37
High-density lipoprotein and transport of cholesterol and triglyceride in blood
Brown, W. V. (2007) · Journal of clinical lipidology · doi:10.1016/j.jacl.2007.02.001 · Cited by 42
APOEgene and neuropsychiatric disorders and endophenotypes: A comprehensive review
Forero, D. A., López‐León, S., González‐Giraldo, Y., Dries, D. R., Pereira‐Morales, A. J., Jiménez, K. M., & Franco‐Restrepo, J. E. (2016) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32516 · Cited by 38
“receptor-binding domain (amino acid residues 154–168) and a major lipid-binding domain (amino acid residues 262–290), connected by a hinge region (amino acid residues 184–242) [Hatters et al., 2006; Frieden and Garai, 2013; Giau et al., 2015].”
BackgroundInfluentialThe APOE ε2 Allele Increases the Risk of Earlier Age at Onset in Machado-Joseph Disease
Bettencourt, C. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.636 · Cited by 41
“Although apoE3 and apoE4 bind to low-density lipoprotein receptors with similarly high affinity, apoE2 has a 50- to 100-fold weaker affinity.(18,19) In the central nervous system, apoE is secreted by astrocytes and is highly expressed in intracellular and extracellular spaces,(20) constituting an important mediator of…”
BackgroundZeng, S., Jiang, J.-X., Xu, M., Xu, L., Shen, G.-J., Zhang, A., & Wang, X. (2014) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2013.0421 · Cited by 38
“Discussion APOE, a key class of lipoproteins found in the brain and CSF, functions as a mediator of cholesterol and lipid transport in cell maintenance and growth (Maysinger et al. , 2008).”
Dafnis, I., Argyri, L., Sagnou, M., Tzinia, A., Tsilibary, E. C., Stratikos, E., & Chroni, A. (2016) · Scientific Reports · doi:10.1038/srep30654 · Cited by 38
“ApoE4 has been described to have both structural and functional differences to apoE2 and apoE3 and some of these differences have been attributed to different interactions between the amino-terminal and carboxyl-terminal domains of the molecule 26,27 .”
InfluentialConcerning the structure of apoE
Frieden, C., & Garai, K. (2013) · Protein Science · doi:10.1002/pro.2379 · Cited by 39
“and apoE4 suggesting the importance of a salt bridge between Arg61 and Glu255 in apoE4 that was proposed not to exist in apoE3.(21) Dong and Weisgraber showed that mutation of Glu255 alters the preference of apoE4 from VLDL to high density lipoprotein (HDL) similar to what would be expected for apoE3.”
Georgiadou, D., Stamatakis, K., Efthimiadou, E. K., Kordas, G., Gantz, D., Chroni, A., & Stratikos, E. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m030965 · Cited by 37
Gallstone disease and mortality: a cohort study
Shabanzadeh, D. M., Sørensen, L. T., & Jørgensen, T. (2016) · International Journal of Public Health · doi:10.1007/s00038-016-0916-7 · Cited by 37
“The underlying mechanisms are not completely understood (Bennet et al. 2007); however, altered affinity to the low density lipoprotein receptor has been suggested (Hatters et al. 2006).”
BackgroundApolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β
Chai, A. B., Lam, H. H. J., Kockx, M., & Gelissen, I. C. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2021.158980 · Cited by 41
Behavioral phenotype and BDNF differences related to apoE isoforms and sex in young transgenic mice
Reverte, I., Klein, A. B., Ratner, C., Domingo, J. L., & Colomina, M. T. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.06.015 · Cited by 41
“ApoE4 is a genetic risk factor that increases the vulnerability to develop AD in the elderly (Hatters et al., 2006; Raber, 2004; Reitz and Mayeux, 2009).”
Effects of Lead and Mercury on the Blood Proteome of Children
Birdsall, R. E., Kiley, M. P., Segu, Z. M., Palmer, C. D., Maděra, M., Gump, B. B., MacKenzie, J. A., Parsons, P. J., Mechref, Y. S., Novotný, M. V., et al. (2010) · Journal of Proteome Research · doi:10.1021/pr100204g · Cited by 37
Evaluation of annexin A5 as a biomarker for Alzheimer's disease and dementia with lewy bodies
Sohma, H., Imai, S.-I., Takei, N., Honda, H., Matsumoto, K., Utsumi, K., Matsuki, K., Hashimoto, E., Saito, T., & Kokai, Y. (2013) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2013.00015 · Cited by 39
“ApoE, which is a major component of lipoproteins, is comprised of 299 amino acid residues and plays a role in the metabolism and redistribution of cholesterol (Hatters et al., 2006).”
BackgroundGenetic Factors Affecting Late-Onset Alzheimer’s Disease Susceptibility
Rezazadeh, M., Khorrami, A., Yeghaneh, T., Talebi, M., Kiani, S. J., Heshmati, Y., & Gharesouran, J. (2015) · NeuroMolecular Medicine · doi:10.1007/s12017-015-8376-4 · Cited by 37
“APOE e4, compared with APOE e3 and APOE e2, has less three-dimensional folding stability (Koren et al., 2009; Mahley and Huang 2006; Hatters et al. 2006).”
BackgroundWang, H., Eschweiler, J. D., Cui, W., Zhang, H., Frieden, C., Ruotolo, B. T., & Gross, M. L. (2019) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-019-02148-z · Cited by 37
“In contrast to a proposed WT structure [2], the NMR structure of apoE3MM shows extensive salt-bridging and hydrogen bonding between the N-terminal and C-terminal domains [14].”
InfluentialLima, D., Hacke, A. C. M., Inaba, J., Pessôa, C. A., & Kerman, K. (2019) · Bioelectrochemistry · doi:10.1016/j.bioelechem.2019.107447 · Cited by 37
Cholesterol in Alzheimer’s Disease and other Amyloidogenic Disorders
Harris, J. R., & Milton, N. G. N. (2010) · Subcellular Biochemistry · doi:10.1007/978-90-481-8622-8_2 · Cited by 44
The effect of Galleria mellonella apolipophorin III on yeasts and filamentous fungi
Zdybicka‐Barabas, A., Stączek, S., Mak, P., Piersiak, T., Skrzypiec, K., & Cytryńska, M. (2011) · Journal of Insect Physiology · doi:10.1016/j.jinsphys.2011.11.003 · Cited by 35
Kern, S., Mehlig, K., Kern, J., Zetterberg, H., Thelle, D. S., Skoog, I. G., Lissner, L., Blennow, K., & Börjesson‐Hanson, A. (2015) · American Journal of Epidemiology · doi:10.1093/aje/kwu442 · Cited by 35
The Interplay Between Apolipoprotein E4 and the Autophagic–Endocytic–Lysosomal Axis
Schmukler, E., Michaelson, D. M., & Pinkas-Kramarski, R. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0892-4 · Cited by 35
“Additional diversities between the apoE isoforms relate to molecular stability, with apoE4 preferentially forming an unstable Bmolten globule^ state [19].”
BackgroundAbbate, J. M., Macrı̀, F., Capparucci, F., Iaria, C., Briguglio, G., Cicero, L. L., Salvo, A., Arfuso, F., Ieni, A., Piccione, G. G., et al. (2020) · Animals · doi:10.3390/ani10122303 · Cited by 35
“Apolipoprotein E (Apo E) is a multifunctional protein that is mainly involved in the maintenance of plasma lipid homeostasis, which participates in the distribution/redistribution of lipids [16].”
BackgroundThe role of full-length apoE in clearance of Gram-negative bacteria and their endotoxins
Petruk, G., Elvén, M., Hartman, E., Davoudi, M., Schmidtchen, A., Puthia, M., & Petrlová, J. (2021) · Journal of Lipid Research · doi:10.1016/j.jlr.2021.100086 · Cited by 33
Valkenburgh, J. S. V., Meuret, C. J., Martinez, A. E., Kodancha, V., Solomon, V. A., Chen, K., & Yassine, H. N. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.700847 · Cited by 38
Lipoprotein assembly and function in an evolutionary perspective
HORST, D. J. V. D., & Rodenburg, K. W. (2010) · BioMolecular Concepts · doi:10.1515/bmc.2010.012 · Cited by 32
APOE 4 polymorphism results in early cognitive deficits in an EAE model
Tu, J.-L., Zhao, C.-B., Vollmer, T., Coons, S., Lin, H.-J., Marsh, S., Treiman, D. M., & Shi, J. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.04.153 · Cited by 29
Metadata
- Authors
- Hatters, D. M., Peters-Libeu, C. A., & Weisgraber, K. H.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Weisgraber, Karl H.
- ORCID
- Hatters, Danny M.
- Venue
- Trends in Biochemical Sciences
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 31
- Issue
- 8
- Pages
- 445-454
- ISSN
- 0968-0004 (ISSN-L)
- OpenAlex
- W2051394059
- Cited by
- 583
- References
- 88
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 26 · 2023: 32 · 2022: 34 · 2021: 37 · 2020: 22 · 2019: 21 · 2018: 24 · 2017: 25 · 2016: 32 · 2015: 32 · 2014: 42 · 2013: 24 · 2012: 42
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Trends in Biochemical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG020235, P01AG022074)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, protein structure, APOE isoforms, low-density lipoprotein receptor family, lipid transport, atherosclerosis, Alzheimer's disease, neurodegenerative diseases, central nervous system, treatment options
- MeSH terms
- Animals, Apolipoproteins E, Humans, Models, Molecular, Protein Binding, Protein Folding, Neurodegenerative Diseases, Protein Isoforms, Atherosclerosis
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