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Cited by 353Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics

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Husain, Mohammed Amir, Laurent, Benoit, Plourde, Mélanie·2021·Frontiers in Neuroscience
DOI 10.3389/fnins.2021.630502PMC PMC7925634
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Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid β (Aβ) and intraneuronal tau protein aggregations. One risk factor for developing AD is the APOE gene coding for the apolipoprotein E protein (apoE). Humans have three versions of APOE gene: ε2, ε3, and ε4 allele. Carrying the ε4 allele is an AD risk factor while carrying the ε2 allele is protective. ApoE is a component of lipoprotein particles in the plasma at the periphery, as well as in the cerebrospinal fluid (CSF) and in the interstitial fluid (ISF) of brain parenchyma in the central nervous system (CNS). ApoE is a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the CNS, and that regulates multiple important signaling pathways. This review will focus on the critical role of apoE in AD pathogenesis and some of the currently apoE-based therapeutics developed in the treatment of AD.

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  • ApoE4 is associated with neurodegeneration, neurotoxicity, synaptic changes, aging and cognitive impairments independently of Aβ.

    “some studies have shown an association of ApoE4 per se with neurodegeneration, neurotoxicity, synaptic changes, aging and cognitive impairments [40].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [40]

    In “APOE Isoforms and AD Physiopathology” (page unavailable), the review links apoE4 to synaptic integrity, cognitive deficits and tau pathology, and Figure 3 explicitly describes Aβ-independent roles for apoE. Its discussion of aging describes a possible loss of mechanisms that compensate for impaired apoE4 lipid transport. The copy does not clearly establish the claimed associations with neurodegeneration or neurotoxicity independently of Aβ. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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  1. Achariyar T. M. Li B. Peng W. Verghese P. B. Shi Y. McConnell E. (2016). Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol. Neurodegener. 11 1– 20. 10.1186/s13024-016-0138-8 27931262 PMC5146863 · DOI
  2. Aizenstein H. J. Nebes R. D. Saxton J. A. Price J. C. Mathis C. A. Tsopelas N. D. (2008). Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch. Neurol. 65 1509– 1517. 10.1001/archneur.65.11.1509 19001171 PMC2636844 · DOI · Paper page
  3. Altmann A. Tian L. Henderson V. W. Greicius M. D. Investigators A. D. N. I. (2014). Sex modifies the APOE-related risk of developing Alzheimer disease. Ann. Neurol. 75 563– 573. 10.1002/ana.24135 24623176 PMC4117990 · DOI · Paper page
  4. Ancelin M.-L. Ripoche E. Dupuy A.-M. Samieri C. Rouaud O. Berr C. (2014). Gender-specific associations between lipids and cognitive decline in the elderly. Eur. Neuropsychopharmacol. 24 1056– 1066. 10.1016/j.euroneuro.2014.02.003 24721317 · DOI
  5. Arenaza-Urquijo E. M. Przybelski S. A. Lesnick T. L. Graff-Radford J. Machulda M. M. Knopman D. S. (2019). The metabolic brain signature of cognitive resilience in the 80+: beyond Alzheimer pathologies. Brain 142 1134– 1147. 10.1093/brain/awz037 30851100 PMC6439329 · DOI
  6. Baker-Nigh A. T. Mawuenyega K. G. Bollinger J. G. Ovod V. Kasten T. Franklin E. E. (2016). Human central nervous system (CNS) ApoE isoforms are increased by age, differentially altered by amyloidosis, and relative amounts reversed in the CNS compared with plasma. J. Biol. Chem. 291 27204– 27218. 10.1074/jbc.m116.721779 27793990 PMC5207148 · DOI · Paper page
  7. Barnes L. L. Wilson R. S. Bienias J. L. Schneider J. A. Evans D. A. Bennett D. A. (2005). Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry 62 685– 691. 10.1001/archpsyc.62.6.685 15939846 · DOI · Paper page
  8. Belloy M. E. Napolioni V. Greicius M. D. (2019). A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron 101 820– 838. 10.1016/j.neuron.2019.01.056 30844401 PMC6407643 · DOI · Paper page
  9. Boehm-Cagan A. Bar R. Liraz O. Bielicki J. K. Johansson J. O. Michaelson D. M. (2016). ABCA1 agonist reverses the ApoE4-driven cognitive and brain pathologies. J. Alzheimers Dis. 54 1219– 1233. 10.3233/jad-160467 27567858 · DOI · Paper page
  10. Boisvert M. M. Erikson G. A. Shokhirev M. N. Allen N. J. (2018). The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep. 22 269– 285. 10.1016/j.celrep.2017.12.039 29298427 PMC5783200 · DOI · Paper page
  11. Brodbeck J. McGuire J. Liu Z. Meyer-Franke A. Balestra M. E. Jeong D. (2011). Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors. J. Biol. Chem. 286 17217– 17226. 10.1074/jbc.m110.217380 21454574 PMC3089564 · DOI · Paper page
  12. Bu G. (2009). Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10 333– 344. 10.1038/nrn2620 19339974 PMC2908393 · DOI · Paper page
  13. Cam J. A. Bu G. (2006). Modulation of β-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family. Mol. Neurodegener. 1 1– 13. 10.1186/1750-1326-1-8 16930455 PMC1563464 · DOI · Paper page
  14. Cam J. A. Zerbinatti C. V. Knisely J. M. Hecimovic S. Li Y. Bu G. (2004). The low density lipoprotein receptor-related protein 1B retains β-amyloid precursor protein at the cell surface and reduces amyloid-β peptide production. J. Biol. Chem. 279 29639– 29646. 10.1074/jbc.m313893200 15126508 · DOI
  15. Cao J. El Gaamouch F. Meabon J. S. Meeker K. D. Zhu L. Zhong M. B. (2017). ApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury. Sci. Rep. 7 1– 12. 10.1038/s41598-017-11654-7 28900205 PMC5595858 · DOI · Paper page
  16. Cesa L. C. Mapp A. K. Gestwicki J. E. (2015). Direct and propagated effects of small molecules on protein–protein interaction networks. Front. Bioeng. Biotechnol. 3: 119. 10.3389/fbioe.2015.00119 26380257 PMC4547496 · DOI
  17. Chen Y. Durakoglugil M. S. Xian X. Herz J. (2010). ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc. Natl. Acad. Sci. U.S.A. 107 12011– 12016. 10.1073/pnas.0914984107 20547867 PMC2900641 · DOI · Paper page
  18. Chernick D. Ortiz-Valle S. Jeong A. Qu W. Li L. (2019). Peripheral versus central nervous system APOE in Alzheimer’s disease: interplay across the blood-brain barrier. Neurosci. Lett. 708: 134306. 10.1016/j.neulet.2019.134306 31181302 PMC6693948 · DOI
  19. Chernick D. Ortiz-Valle S. Jeong A. Swaminathan S. K. Kandimalla K. K. Rebeck G. W. (2018). High-density lipoprotein mimetic peptide 4F mitigates amyloid-β-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia. J. Neurochem. 147 647– 662. 10.1111/jnc.14554 30028014 PMC6314045 · DOI
  20. Chew H. Solomon V. A. Fonteh A. N. (2020). Involvement of lipids in Alzheimer’s disease pathology and potential therapies. Front. Physiol. 11: 598. 10.3389/fphys.2020.00598 32581851 PMC7296164 · DOI · Paper page
  21. Chouinard-Watkins R. Rioux-Perreault C. Fortier M. Tremblay-Mercier J. Zhang Y. Lawrence P. (2013). Disturbance in uniformly 13 C-labelled DHA metabolism in elderly human subjects carrying the apoE ε4 allele. Br. J. Nutr. 110 1751– 1759. 10.1017/s0007114513001268 23631810 · DOI
  22. Christensen E. I. Gliemann J. Moestrup S. K. (1992). Renal tubule gp330 is a calcium binding receptor for endocytic uptake of protein. J. Histochem. Cytochem. 40 1481– 1490. 10.1177/40.10.1382088 1382088 · DOI
  23. Corbo R. M. Scacchi R. (1999). Apolipoprotein E (APOE) allele distribution in the world. Is APOE∗ 4 a ‘thrifty’allele? Ann. Hum. Genet. 63 301– 310. 10.1046/j.1469-1809.1999.6340301.x 10738542 · DOI
  24. Corder E. H. Ghebremedhin E. Taylor M. G. Thal D. R. Ohm T. G. Braak H. (2004). The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann. N. Y. Acad. Sci. 1019 24– 28. 10.1196/annals.1297.005 15246987 · DOI · Paper page
  25. Cruchaga C. Kauwe J. S. Nowotny P. Bales K. Pickering E. H. Mayo K. (2012). Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer’s disease. Hum. Mol. Genet. 21 4558– 4571. 10.1093/hmg/dds296 22821396 PMC3459471 · DOI · Paper page
  26. Cui W. Sun Y. Wang Z. Xu C. Xu L. Wang F. (2011). Activation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels. Neurochem. Res. 36 1910– 1921. 10.1007/s11064-011-0513-3 21630010 · DOI
  27. Dlugosz P. Nimpf J. (2018). The reelin receptors apolipoprotein E receptor 2 (ApoER2) and VLDL receptor. Int. J. Mol. Sci. 19: 3090. 10.3390/ijms19103090 30304853 PMC6213145 · DOI · Paper page
  28. dos Santos Rodrigues B. Kanekiyo T. Singh J. (2019). ApoE-2 brain-targeted gene therapy through transferrin and penetratin tagged liposomal nanoparticles. Pharm. Res. 36: 161. 10.1007/s11095-019-2691-7 31529284 PMC10150442 · DOI
  29. Egert S. Rimbach G. Huebbe P. (2012). ApoE genotype: from geographic distribution to function and responsiveness to dietary factors. Proc. Nutr. Soc. 71 410– 424. 10.1017/s0029665112000249 22564824 · DOI
  30. Etique N. Verzeaux L. Dedieu S. Emonard H. (2013). LRP-1: a checkpoint for the extracellular matrix proteolysis. BioMed Res. Int. 2013: 152163. 10.1155/2013/152163 23936774 PMC3723059 · DOI
  31. Flowers S. A. Rebeck G. W. (2020). APOE in the normal brain. Neurobiol. Dis. 136: 104724. 10.1016/j.nbd.2019.104724 31911114 PMC7002287 · DOI · Paper page
  32. Frieden C. Garai K. (2012). Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 109 8913– 8918. 10.1073/pnas.1207022109 22615372 PMC3384159 · DOI · Paper page
  33. Gilat-Frenkel M. Boehm-Cagan A. Liraz O. Xian X. Herz J. Michaelson D. M. (2014). Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo. Curr. Alzheimer Res. 11 549– 557. 10.2174/1567205010666131119232444 24251389 PMC4065855 · DOI
  34. Gottschalk W. K. Mihovilovic M. Roses A. D. Chiba-Falek O. (2016). The role of upregulated APOE in Alzheimer’s disease etiology. J. Alzheimers Dis. Park. 6: 209. 10.4172/2161-0460.1000209 27104063 PMC4836841 · DOI
  35. Guptill J. T. Raja S. M. Boakye-Agyeman F. Noveck R. Ramey S. Tu T. M. (2017). Phase 1 randomized, double-blind, placebo-controlled study to determine the safety, tolerability, and pharmacokinetics of a single escalating dose and repeated doses of CN-105 in healthy adult subjects. J. Clin. Pharmacol. 57 770– 776. 10.1002/jcph.853 27990643 PMC5524215 · DOI
  36. Hauser P. S. Narayanaswami V. Ryan R. O. (2011). Apolipoprotein E: from lipid transport to neurobiology. Prog. Lipid Res. 50 62– 74. 10.1016/j.plipres.2010.09.001 20854843 PMC3022415 · DOI · Paper page
  37. Hinrich A. J. Jodelka F. M. Chang J. L. Brutman D. Bruno A. M. Briggs C. A. (2016). Therapeutic correction of ApoER2 splicing in Alzheimer’s disease mice using antisense oligonucleotides. EMBO Mol. Med. 8 328– 345. 10.15252/emmm.201505846 26902204 PMC4818756 · DOI · Paper page
  38. Holtzman D. M. Herz J. Bu G. (2012). Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2: a006312. 10.1101/cshperspect.a006312 22393530 PMC3282491 · DOI · Paper page
  39. Hsu M. Dedhia M. Crusio W. E. Delprato A. (2019). Sex differences in gene expression patterns associated with the APOE4 allele. F1000Research 8: 387. 10.12688/f1000research.18671.2 31448102 PMC6685458 · DOI
  40. Huang Y.-W. A. Zhou B. Wernig M. Südhof T. C. (2017). ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell 168 427– 441. 10.1016/j.cell.2016.12.044 28111074 PMC5310835 · DOI · Paper page
  41. Huang Z. H. Reardon C. A. Getz G. S. Maeda N. Mazzone T. (2015). Selective suppression of adipose tissue apoE expression impacts systemic metabolic phenotype and adipose tissue inflammation. J. Lipid Res. 56 215– 226. 10.1194/jlr.m050567 25421060 PMC4306677 · DOI
  42. Hubin E. Verghese P. B. van Nuland N. Broersen K. (2019). Apolipoprotein E associated with reconstituted high-density lipoprotein-like particles is protected from aggregation. FEBS Lett. 593 1144– 1153. 10.1002/1873-3468.13428 31058310 PMC6617784 · DOI · Paper page
  43. Huynh T.-P. V. Liao F. Francis C. M. Robinson G. O. Serrano J. R. Jiang H. (2017). Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron 96 1013– 1023. 10.1016/j.neuron.2017.11.014 29216448 PMC5728673 · DOI · Paper page
  44. Ittner L. M. Klugmann M. Ke Y. D. (2019). Adeno-associated virus-based Alzheimer’s disease mouse models and potential new therapeutic avenues. Br. J. Pharmacol. 176 3649– 3665. 10.1111/bph.14637 30817847 PMC6715621 · DOI
  45. Kanekiyo T. Liu C.-C. Shinohara M. Li J. Bu G. (2012). LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer’s amyloid-β. J. Neurosci. 32 16458– 16465. 10.1523/jneurosci.3987-12.2012 23152628 PMC3508699 · DOI
  46. Kloske C. M. Wilcock D. M. (2020). The important interface between apolipoprotein e and neuroinflammation in Alzheimer’s disease. Front. Immunol. 11: 754. 10.3389/fimmu.2020.00754 PMC7203730 32425941 · DOI · Paper page
  47. Koch S. Donarski N. Goetze K. Kreckel M. Stuerenburg H.-J. Buhmann C. (2001). Characterization of four lipoprotein classes in human cerebrospinal fluid. J. Lipid Res. 42 1143– 1151. 10.1016/s0022-2275(20)31605-9 11441143 · DOI · Paper page
  48. Kockx M. Jessup W. Kritharides L. (2008). Regulation of endogenous apolipoprotein E secretion by macrophages. Arterioscler. Thromb. Vasc. Biol. 28 1060– 1067. 10.1161/atvbaha.108.164350 18388328 · DOI
  49. Kounnas M. Z. Haudenschild C. C. Strickland D. K. Argraves W. S. (1994). Immunological localization of glycoprotein 330, low density lipoprotein receptor related protein and 39 kDa receptor associated protein in embryonic mouse tissues. Vivo Athens Greece 8 343– 351. 7803716
  50. Krishnamurthy K. Cantillana V. Wang H. Sullivan P. M. Kolls B. J. Ge X. (2020). ApoE mimetic improves pathology and memory in a model of Alzheimer’s disease. Brain Res. 1733: 146685. 10.1016/j.brainres.2020.146685 32007397 · DOI · Paper page
  51. Lane-Donovan C. Herz J. (2017). The ApoE receptors Vldlr and Apoer2 in central nervous system function and disease. J. Lipid Res. 58 1036– 1043. 10.1194/jlr.r075507 28292942 PMC5454520 · DOI · Paper page
  52. Laskowitz D. T. Wang H. Chen T. Lubkin D. T. Cantillana V. Tu T. M. (2017). Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model. Sci. Rep. 7: 46461. 10.1038/srep46461 28429734 PMC5399447 · DOI
  53. Lim W. L. F. Huynh K. Chatterjee P. Martins I. Jayawardana K. S. Giles C. (2020). Relationships between plasma lipids species, gender, risk factors, and Alzheimer’s disease. J. Alzheimers Dis. 76 303– 315. 10.3233/jad-191304 32474467 PMC7369125 · DOI
  54. Liu C.-C. Kanekiyo T. Xu H. Bu G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9 106– 118. 10.1038/nrneurol.2012.263 23296339 PMC3726719 · DOI · Paper page
  55. Liu J. Zhou G. Kolls B. J. Tan Y. Fang C. Wang H. (2018). Apolipoprotein E mimetic peptide CN-105 improves outcome in a murine model of SAH. Stroke Vasc. Neurol. 3 222– 230. 10.1136/svn-2018-000152 30637128 PMC6312076 · DOI
  56. Liu S. Breitbart A. Sun Y. Mehta P. D. Boutajangout A. Scholtzova H. (2014). Blocking the apolipoprotein E/amyloid β interaction in triple transgenic mice ameliorates Alzheimer’s disease related amyloid β and tau pathology. J. Neurochem. 128 577– 591. 10.1111/jnc.12484 24117759 PMC3946231 · DOI · Paper page
  57. Lohner S. Fekete K. Marosvölgyi T. Decsi T. (2013). Gender differences in the long-chain polyunsaturated fatty acid status: systematic review of 51 publications. Ann. Nutr. Metab. 62 98– 112. 10.1159/000345599 23327902 · DOI
  58. Mahley R. W. Rall S. C. Jr. (2000). Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1 507– 537. 10.1146/annurev.genom.1.1.507 11701639 · DOI · Paper page
  59. Marottoli F. M. Katsumata Y. Koster K. P. Thomas R. Fardo D. W. Tai L. M. (2017). Peripheral inflammation, apolipoprotein E4, and amyloid-β interact to induce cognitive and cerebrovascular dysfunction. ASN Neuro 9: 1759091417719201 10.1177/1759091417719201 28707482 PMC5521356 · DOI
  60. Marschang P. Brich J. Weeber E. J. Sweatt J. D. Shelton J. M. Richardson J. A. (2004). Normal development and fertility of knockout mice lacking the tumor suppressor gene LRP1b suggest functional compensation by LRP1. Mol. Cell. Biol. 24 3782– 3793. 10.1128/mcb.24.9.3782-3793.2004 15082773 PMC387731 · DOI
  61. Martínez-Morillo E. Hansson O. Atagi Y. Bu G. Minthon L. Diamandis E. P. (2014). Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls. Acta Neuropathol. (Berl.) 127 633– 643. 10.1007/s00401-014-1266-2 24633805 · DOI · Paper page
  62. McIntosh A. M. Bennett C. Dickson D. Anestis S. F. Watts D. P. Webster T. H. (2012). The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes). PLoS One 7: 47760. 10.1371/journal.pone.0047760 23112842 PMC3480407 · DOI
  63. Mesa-Herrera F. Taoro-González L. Valdés-Baizabal C. Diaz M. Marín R. (2019). Lipid and lipid raft alteration in aging and neurodegenerative diseases: a window for the development of new biomarkers. Int. J. Mol. Sci. 20: 3810. 10.3390/ijms20153810 31382686 PMC6696273 · DOI
  64. Nelson T. J. Sen A. (2019). Apolipoprotein E particle size is increased in Alzheimer’s disease. Alzheimers Dement. Diagn. Assess. Dis. Monit. 11 10– 18. 10.1016/j.dadm.2018.10.005 30581971 PMC6293020 · DOI
  65. Nguyen D. Dhanasekaran P. Nickel M. Nakatani R. Saito H. Phillips M. C. (2010). Molecular basis for the differences in lipid and lipoprotein binding properties of human apolipoproteins E3 and E4. Biochemistry 49 10881– 10889. 10.1021/bi1017655 21114327 PMC3025481 · DOI · Paper page
  66. Nickerson D. A. Taylor S. L. Fullerton S. M. Weiss K. M. Clark A. G. Stengård J. H. (2000). Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. Genome Res. 10 1532– 1545. 10.1101/gr.146900 11042151 PMC310963 · DOI
  67. Osei-Hwedieh D. O. Amar M. Sviridov D. Remaley A. T. (2011). Apolipoprotein mimetic peptides: mechanisms of action as anti-atherogenic agents. Pharmacol. Ther. 130 83– 91. 10.1016/j.pharmthera.2010.12.003 21172387 PMC3043134 · DOI
  68. Palmisano B. T. Zhu L. Eckel R. H. Stafford J. M. (2018). Sex differences in lipid and lipoprotein metabolism. Mol. Metab. 15 45– 55. 10.1016/j.molmet.2018.05.008 29858147 PMC6066747 · DOI
  69. Payami H. Montee K. R. Kaye J. A. Bird T. D. Yu C.-E. Wijsman E. M. (1994). Alzheimer’s disease, apolipoprotein E4, and gender. Jama 271 1316– 1317. 10.1001/jama.271.17.1316 8158809 · DOI
  70. Peng D. Song C. Reardon C. A. Liao S. Getz G. S. (2003). Lipoproteins produced by ApoE–/–astrocytes infected with adenovirus expressing human ApoE. J. Neurochem. 86 1391– 1402. 10.1046/j.1471-4159.2003.01950.x 12950448 · DOI
  71. Prasad H. Rao R. (2018). Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH. Proc. Natl. Acad. Sci. U.S.A. 115 E6640– E6649. 10.1073/pnas.1801612115 29946028 PMC6048470 · DOI
  72. Qosa H. Abuznait A. H. Hill R. A. Kaddoumi A. (2012). Enhanced brain amyloid-β clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer’s disease. J. Alzheimers Dis. 31 151– 165. 10.3233/jad-2012-120319 22504320 PMC3902015 · DOI
  73. Rapp A. Gmeiner B. Hüttinger M. (2006). Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes. Biochimie 88 473– 483. 10.1016/j.biochi.2005.10.007 16376010 · DOI
  74. Rawat V. Wang S. Sima J. Bar R. Liraz O. Gundimeda U. (2019). ApoE4 alters ABCA1 membrane trafficking in astrocytes. J. Neurosci. 39 9611– 9622. 10.1523/jneurosci.1400-19.2019 31641056 PMC6880458 · DOI · Paper page
  75. Rebeck G. W. (2017). The role of APOE on lipid homeostasis and inflammation in normal brains. J. Lipid Res. 58 1493– 1499. 10.1194/jlr.r075408 28258087 PMC5538293 · DOI · Paper page
  76. Ruiz J. Kouiavskaia D. Migliorini M. Robinson S. Saenko E. L. Gorlatova N. (2005). The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J. Lipid Res. 46 1721– 1731. 10.1194/jlr.m500114-jlr200 15863833 · DOI · Paper page
  77. Safieh M. Korczyn A. D. Michaelson D. M. (2019). ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC Med. 17: 64. 10.1186/s12916-019-1299-4 30890171 PMC6425600 · DOI · Paper page
  78. Sawmiller D. Habib A. Hou H. Mori T. Fan A. Tian J. (2019). A novel apolipoprotein E antagonist functionally blocks apolipoprotein E interaction with N-terminal amyloid precursor protein, reduces β-amyloid-associated pathology, and improves cognition. Biol. Psychiatry 86 208– 220. 10.1016/j.biopsych.2019.04.026 31208706 PMC6642011 · DOI
  79. Shi Y. Yamada K. Liddelow S. A. Smith S. T. Zhao L. Luo W. (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549 523– 527. 10.1038/nature24016 28959956 PMC5641217 · DOI · Paper page
  80. Shinohara M. Sato N. Kurinami H. Takeuchi D. Takeda S. Shimamura M. (2010). Reduction of brain β-amyloid (Aβ) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and Aβ clearance. J. Biol. Chem. 285 22091– 22102. 10.1074/jbc.m110.102277 20472556 PMC2903370 · DOI
  81. Singh R. K. Haka A. S. Asmal A. Barbosa-Lorenzi V. C. Grosheva I. Chin H. F. (2020). TLR4 (toll-like receptor 4)-dependent signaling drives extracellular catabolism of LDL (low-density lipoprotein) aggregates. Arterioscler. Thromb. Vasc. Biol. 40 86– 102. 10.1161/atvbaha.119.313200 31597445 PMC6928397 · DOI
  82. Solomon A. Turunen H. Ngandu T. Peltonen M. Levälahti E. Helisalmi S. (2018). Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 75 462– 470. 10.1001/jamaneurol.2017.4365 29356827 PMC5885273 · DOI · Paper page
  83. Spuch C. Antequera D. Pascual C. Abilleira S. Blanco M. Moreno-Carretero M. J. (2015). Soluble megalin is reduced in cerebrospinal fluid samples of Alzheimer’s disease patients. Front. Cell. Neurosci. 9: 134. 10.3389/fncel.2015.00134 25926771 PMC4397959 · DOI
  84. Suidan G. L. Ramaswamy G. (2019). Targeting apolipoprotein E for Alzheimer’s disease: an industry perspective. Int. J. Mol. Sci. 20: 2161. 10.3390/ijms20092161 31052389 PMC6539182 · DOI · Paper page
  85. Svennerholm L. Boström K. Jungbjer B. (1997). Changes in weight and compositions of major membrane components of human brain during the span of adult human life of Swedes. Acta Neuropathol. (Berl.) 94 345– 352. 10.1007/s004010050717 9341935 · DOI · Paper page
  86. Tachibana M. Shinohara M. Yamazaki Y. Liu C.-C. Rogers J. Bu G. (2016). Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp. Neurol. 277 1– 9. 10.1016/j.expneurol.2015.12.003 26688581 PMC4761336 · DOI
  87. Talwar P. Sinha J. Grover S. Agarwal R. Kushwaha S. Srivastava M. P. (2016). Meta-analysis of apolipoprotein E levels in the cerebrospinal fluid of patients with Alzheimer’s disease. J. Neurol. Sci. 360 179– 187. 10.1016/j.jns.2015.12.004 26723997 · DOI
  88. Tarasoff-Conway J. M. Carare R. O. Osorio R. S. Glodzik L. Butler T. Fieremans E. (2015). Clearance systems in the brain—implications for Alzheimer disease. Nat. Rev. Neurol. 11: 457. 10.1038/nrneurol.2015.119 26195256 PMC4694579 · DOI · Paper page
  89. Tcw J. Liang S. A. Qian L. Pipalia N. H. Chao M. J. Bertelsen S. E. (2019). Cholesterol and Matrisome Pathways Dysregulated in Human APOE ϵ4 Glia. Rochester, NY: Social Science Research Network. 10.2139/ssrn.3435267 · DOI
  90. Teng Z. Guo Z. Zhong J. Cheng C. Huang Z. Wu Y. (2017). ApoE influences the blood-brain barrier through the NF-κB/MMP-9 pathway after traumatic brain injury. Sci. Rep. 7, 1– 8. 10.1038/s41598-017-06932-3 28751738 PMC5532277 · DOI
  91. Ulrich J. D. Burchett J. M. Restivo J. L. Schuler D. R. Verghese P. B. Mahan T. E. (2013). In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol. Neurodegener. 8 1– 7. 10.1186/1750-1326-8-13 23601557 PMC3640999 · DOI · Paper page
  92. van Veluw S. J. Shih A. Y. Smith E. E. Chen C. Schneider J. A. Wardlaw J. M. (2017). Detection, risk factors, and functional consequences of cerebral microinfarcts. Lancet Neurol. 16 730– 740. 10.1016/s1474-4422(17)30196-5 28716371 PMC5861500 · DOI
  93. Vasilevskaya A. Taghdiri F. Burke C. Tarazi A. Naeimi S. A. Khodadadi M. (2020). Interaction of APOE4 alleles and PET tau imaging in former contact sport athletes. NeuroImage Clin. 26: 102212. 10.1016/j.nicl.2020.102212 32097865 PMC7037542 · DOI
  94. Villeneuve S. Brisson D. Gaudet D. (2015). Influence of abdominal obesity on the lipid-lipoprotein profile in apoprotein E2/4 carriers: the effect of an apparent duality. J. Lipids 2015: 742408. 10.1155/2015/742408 26605088 PMC4641183 · DOI
  95. Williams H. C. Farmer B. C. Piron M. A. Walsh A. E. Bruntz R. C. Gentry M. S. (2020). APOE alters glucose flux through central carbon pathways in astrocytes. Neurobiol. Dis. 136: 104742. 10.1016/j.nbd.2020.104742 31931141 PMC7044721 · DOI · Paper page
  96. Wolters F. J. Yang Q. Biggs M. L. Jakobsdottir J. Li S. Evans D. S. (2019). The impact of APOE genotype on survival: results of 38,537 participants from six population-based cohorts (E2-CHARGE). PLoS One 14: e0219668. 10.1371/journal.pone.0219668 31356640 PMC6663005 · DOI · Paper page
  97. Yajima R. Tokutake T. Koyama A. Kasuga K. Tezuka T. Nishizawa M. (2015). ApoE-isoform-dependent cellular uptake of amyloid-β is mediated by lipoprotein receptor LR11/SorLA. Biochem. Biophys. Res. Commun. 456 482– 488. 10.1016/j.bbrc.2014.11.111 25482438 · DOI · Paper page
  98. Yamazaki Y. Zhao N. Caulfield T. R. Liu C.-C. Bu G. (2019). Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15 501– 518. 10.1038/s41582-019-0228-7 31367008 PMC7055192 · DOI · Paper page
  99. Yang Y. G. Kim J. Y. Park S. J. Kim S. W. Jeon O. H. Kim D. S. (2007). Apolipoprotein E genotyping by multiplex tetra-primer amplification refractory mutation system PCR in single reaction tube. J. Biotechnol. 131 106– 110. 10.1016/j.jbiotec.2007.06.001 17643539 · DOI
  100. Yao X. Vitek M. P. Remaley A. T. Levine S. J. (2012). Apolipoprotein mimetic peptides: a new approach for the treatment of asthma. Front. Pharmacol. 3: 37. 10.3389/fphar.2012.00037 22408624 PMC3297834 · DOI
  101. Yassine H. N. Feng Q. Chiang J. Petrosspour L. M. Fonteh A. N. Chui H. C. (2016). ABCA1-mediated cholesterol efflux capacity to cerebrospinal fluid is reduced in patients with mild cognitive impairment and alzheimer’s disease. J. Am. Heart Assoc. 5: e002886. 10.1161/JAHA.115.002886 26873692 PMC4802440 · DOI · Paper page
  102. Yassine H. N. Finch C. E. (2020). APOE alleles and diet in brain aging and Alzheimer’s disease. Front. Aging Neurosci. 12: 150. 10.3389/fnagi.2020.00150 PMC7297981 32587511 · DOI · Paper page
  103. Zhao J. Davis M. D. Martens Y. A. Shinohara M. Graff-Radford N. R. Younkin S. G. (2017). APOE ε4/ε4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum. Mol. Genet. 26 2690– 2700. 10.1093/hmg/ddx155 28444230 PMC5886091 · DOI · Paper page
  104. Zhao L. Gottesdiener A. J. Parmar M. Li M. Kaminsky S. M. Chiuchiolo M. J. (2016). Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer’s disease mouse models. Neurobiol. Aging 44 159– 172. 10.1016/j.neurobiolaging.2016.04.020 27318144 · DOI · Paper page
  105. Zhao N. Liu C.-C. Qiao W. Bu G. (2018a). Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol. Psychiatry 83 347– 357. 10.1016/j.biopsych.2017.03.003 28434655 PMC5599322 · DOI · Paper page

Cited by

Sorted by citations

Authors
Husain, M. A., Laurent, B., & Plourde, M.
Affiliations
Université de Sherbrooke (CA)
Corresponding author
Plourde, Mélanie
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2021-02-17
Volume
15
Pages
630502-630502
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2021.630502
PMC
PMC7925634
OpenAlex
W3130526148
Cited by
353
References
41
Citations by year
2026: 72 · 2025: 82 · 2024: 77 · 2023: 59 · 2022: 52 · 2021: 11
FWCI
6.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Université de Sherbrooke
  • Canadian Institutes of Health Research
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, apolipoprotein E, APOE ε4, amyloid-beta, tau aggregation, lipid transport, lipoproteins, cerebrospinal fluid, interstitial fluid, AD pathogenesis

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