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. 1996 Mar;21(2):128–134.

Apolipoprotein E in the brain and its role in Alzheimer's disease.

J Poirier 1
PMCID: PMC1188752  PMID: 8820179

Abstract

Recent evidence indicates that apolipoprotein E (apoE) plays a central role in the brain response to injury. The coordinated expression of apoE and its main receptor, the apoE/apoB (LDL) receptor, appears to regulate the transport of cholesterol and phospholipids during the different phases of the reinnervation process. The recent discovery that a peculiar form of apoE, the apoE4, is strongly linked to both sporadic and familial late onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system associated with compensatory sprouting and synaptic remodelling could be central to the AD process. The role of apoE in the central nervous system (CNS) is particularly important in relation to the function of the cholinergic system which relies to a certain extent on the integrity of phospholipid homeostasis in neurons. Recent evidence suggests that apoE4 allele has a direct impact on cholinergic function in AD.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blennow K., Hesse C., Fredman P. Cerebrospinal fluid apolipoprotein E is reduced in Alzheimer's disease. Neuroreport. 1994 Dec 20;5(18):2534–2536. doi: 10.1097/00001756-199412000-00032. [DOI] [PubMed] [Google Scholar]
  2. Boyles J. K., Zoellner C. D., Anderson L. J., Kosik L. M., Pitas R. E., Weisgraber K. H., Hui D. Y., Mahley R. W., Gebicke-Haerter P. J., Ignatius M. J. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest. 1989 Mar;83(3):1015–1031. doi: 10.1172/JCI113943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Breteler M. M., Claus J. J., van Duijn C. M., Launer L. J., Hofman A. Epidemiology of Alzheimer's disease. Epidemiol Rev. 1992;14:59–82. doi: 10.1093/oxfordjournals.epirev.a036092. [DOI] [PubMed] [Google Scholar]
  4. Brown M. S., Dana S. E., Goldstein J. L. Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts by lipoproteins. Proc Natl Acad Sci U S A. 1973 Jul;70(7):2162–2166. doi: 10.1073/pnas.70.7.2162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brown M. S., Goldstein J. L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986 Apr 4;232(4746):34–47. doi: 10.1126/science.3513311. [DOI] [PubMed] [Google Scholar]
  6. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., Pericak-Vance M. A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
  7. Davies P., Maloney A. J. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet. 1976 Dec 25;2(8000):1403–1403. doi: 10.1016/s0140-6736(76)91936-x. [DOI] [PubMed] [Google Scholar]
  8. Davignon J., Gregg R. E., Sing C. F. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988 Jan-Feb;8(1):1–21. doi: 10.1161/01.atv.8.1.1. [DOI] [PubMed] [Google Scholar]
  9. Flood D. G., Coleman P. D. Failed compensatory dendritic growth as a pathophysiological process in Alzheimer's disease. Can J Neurol Sci. 1986 Nov;13(4 Suppl):475–479. doi: 10.1017/s031716710003715x. [DOI] [PubMed] [Google Scholar]
  10. Geddes J. W., Monaghan D. T., Cotman C. W., Lott I. T., Kim R. C., Chui H. C. Plasticity of hippocampal circuitry in Alzheimer's disease. Science. 1985 Dec 6;230(4730):1179–1181. doi: 10.1126/science.4071042. [DOI] [PubMed] [Google Scholar]
  11. Gerdes L. U., Klausen I. C., Sihm I., Faergeman O. Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet Epidemiol. 1992;9(3):155–167. doi: 10.1002/gepi.1370090302. [DOI] [PubMed] [Google Scholar]
  12. Goodrum J. F. Cholesterol synthesis is down-regulated during regeneration of peripheral nerve. J Neurochem. 1990 May;54(5):1709–1715. doi: 10.1111/j.1471-4159.1990.tb01225.x. [DOI] [PubMed] [Google Scholar]
  13. Hyman B. T., Kromer L. J., Van Hoesen G. W. Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease. Ann Neurol. 1987 Mar;21(3):259–267. doi: 10.1002/ana.410210307. [DOI] [PubMed] [Google Scholar]
  14. Hyman B. T., Van Hoesen G. W., Damasio A. R., Barnes C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science. 1984 Sep 14;225(4667):1168–1170. doi: 10.1126/science.6474172. [DOI] [PubMed] [Google Scholar]
  15. Jones O. T., McNamee M. G. Annular and nonannular binding sites for cholesterol associated with the nicotinic acetylcholine receptor. Biochemistry. 1988 Apr 5;27(7):2364–2374. doi: 10.1021/bi00407a018. [DOI] [PubMed] [Google Scholar]
  16. Kowal R. C., Herz J., Goldstein J. L., Esser V., Brown M. S. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810–5814. doi: 10.1073/pnas.86.15.5810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kuusisto J., Koivisto K., Kervinen K., Mykkänen L., Helkala E. L., Vanhanen M., Hänninen T., Pyörälä K., Kesäniemi Y. A., Riekkinen P. Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study. BMJ. 1994 Sep 10;309(6955):636–638. doi: 10.1136/bmj.309.6955.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lee H. C., Fellenz-Maloney M. P., Liscovitch M., Blusztajn J. K. Phospholipase D-catalyzed hydrolysis of phosphatidylcholine provides the choline precursor for acetylcholine synthesis in a human neuronal cell line. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10086–10090. doi: 10.1073/pnas.90.21.10086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lucotte G., David F., Visvikis S., Leininger-Müller B., Siest G., Babron M. C., Couderc R. Apolipoprotein E-epsilon 4 allele and Alzheimer's disease. Lancet. 1993 Nov 20;342(8882):1309–1309. [PubMed] [Google Scholar]
  20. Matthews D. A., Cotman C., Lynch G. An electron microscopic study of lesion-induced synaptogenesis in the dentate gyrus of the adult rat. II. Reappearance of morphologically normal synaptic contacts. Brain Res. 1976 Oct 8;115(1):23–41. doi: 10.1016/0006-8993(76)90820-9. [DOI] [PubMed] [Google Scholar]
  21. Nalbantoglu J., Gilfix B. M., Bertrand P., Robitaille Y., Gauthier S., Rosenblatt D. S., Poirier J. Predictive value of apolipoprotein E genotyping in Alzheimer's disease: results of an autopsy series and an analysis of several combined studies. Ann Neurol. 1994 Dec;36(6):889–895. doi: 10.1002/ana.410360614. [DOI] [PubMed] [Google Scholar]
  22. Nathan B. P., Bellosta S., Sanan D. A., Weisgraber K. H., Mahley R. W., Pitas R. E. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science. 1994 May 6;264(5160):850–852. doi: 10.1126/science.8171342. [DOI] [PubMed] [Google Scholar]
  23. Nitsch R. M., Blusztajn J. K., Pittas A. G., Slack B. E., Growdon J. H., Wurtman R. J. Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1671–1675. doi: 10.1073/pnas.89.5.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Okuizumi K., Onodera O., Tanaka H., Kobayashi H., Tsuji S., Takahashi H., Oyanagi K., Seki K., Tanaka M., Naruse S. ApoE-epsilon 4 and early-onset Alzheimer's. Nat Genet. 1994 May;7(1):10–11. doi: 10.1038/ng0594-10b. [DOI] [PubMed] [Google Scholar]
  25. Olaisen B., Teisberg P., Gedde-Dahl T., Jr The locus for apolipoprotein E (apoE) is linked to the complement component C3 (C3) locus on chromosome 19 in man. Hum Genet. 1982;62(3):233–236. doi: 10.1007/BF00333526. [DOI] [PubMed] [Google Scholar]
  26. Paik Y. K., Chang D. J., Reardon C. A., Davies G. E., Mahley R. W., Taylor J. M. Nucleotide sequence and structure of the human apolipoprotein E gene. Proc Natl Acad Sci U S A. 1985 May;82(10):3445–3449. doi: 10.1073/pnas.82.10.3445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Payami H., Kaye J., Heston L. L., Bird T. D., Schellenberg G. D. Apolipoprotein E genotype and Alzheimer's disease. Lancet. 1993 Sep 18;342(8873):738–738. [PubMed] [Google Scholar]
  28. Perry E. K., Gibson P. H., Blessed G., Perry R. H., Tomlinson B. E. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci. 1977 Nov;34(2):247–265. doi: 10.1016/0022-510x(77)90073-9. [DOI] [PubMed] [Google Scholar]
  29. Poirier J. Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci. 1994 Dec;17(12):525–530. doi: 10.1016/0166-2236(94)90156-2. [DOI] [PubMed] [Google Scholar]
  30. Poirier J., Baccichet A., Dea D., Gauthier S. Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neuroscience. 1993 Jul;55(1):81–90. doi: 10.1016/0306-4522(93)90456-p. [DOI] [PubMed] [Google Scholar]
  31. Poirier J., Davignon J., Bouthillier D., Kogan S., Bertrand P., Gauthier S. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet. 1993 Sep 18;342(8873):697–699. doi: 10.1016/0140-6736(93)91705-q. [DOI] [PubMed] [Google Scholar]
  32. Poirier J., Hess M., May P. C., Finch C. E. Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. Brain Res Mol Brain Res. 1991 Sep;11(2):97–106. doi: 10.1016/0169-328x(91)90111-a. [DOI] [PubMed] [Google Scholar]
  33. Popko B., Goodrum J. F., Bouldin T. W., Zhang S. H., Maeda N. Nerve regeneration occurs in the absence of apolipoprotein E in mice. J Neurochem. 1993 Mar;60(3):1155–1158. doi: 10.1111/j.1471-4159.1993.tb03268.x. [DOI] [PubMed] [Google Scholar]
  34. Rall S. C., Jr, Weisgraber K. H., Mahley R. W. Human apolipoprotein E. The complete amino acid sequence. J Biol Chem. 1982 Apr 25;257(8):4171–4178. [PubMed] [Google Scholar]
  35. Ransmayr G., Cervera P., Hirsch E., Ruberg M., Hersh L. B., Duyckaerts C., Hauw J. J., Delumeau C., Agid Y. Choline acetyltransferase-like immunoreactivity in the hippocampal formation of control subjects and patients with Alzheimer's disease. Neuroscience. 1989;32(3):701–714. doi: 10.1016/0306-4522(89)90291-1. [DOI] [PubMed] [Google Scholar]
  36. Rebeck G. W., Reiter J. S., Strickland D. K., Hyman B. T. Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron. 1993 Oct;11(4):575–580. doi: 10.1016/0896-6273(93)90070-8. [DOI] [PubMed] [Google Scholar]
  37. Saunders A. M., Strittmatter W. J., Schmechel D., George-Hyslop P. H., Pericak-Vance M. A., Joo S. H., Rosi B. L., Gusella J. F., Crapper-MacLachlan D. R., Alberts M. J. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993 Aug;43(8):1467–1472. doi: 10.1212/wnl.43.8.1467. [DOI] [PubMed] [Google Scholar]
  38. Strittmatter W. J., Weisgraber K. H., Goedert M., Saunders A. M., Huang D., Corder E. H., Dong L. M., Jakes R., Alberts M. J., Gilbert J. R. Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp Neurol. 1994 Feb;125(2):163–174. doi: 10.1006/exnr.1994.1019. [DOI] [PubMed] [Google Scholar]
  39. Südhof T. C., Goldstein J. L., Brown M. S., Russell D. W. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985 May 17;228(4701):815–822. doi: 10.1126/science.2988123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Utermann G. Apolipoprotein E polymorphism in health and disease. Am Heart J. 1987 Feb;113(2 Pt 2):433–440. doi: 10.1016/0002-8703(87)90610-7. [DOI] [PubMed] [Google Scholar]
  41. Wilson C., Wardell M. R., Weisgraber K. H., Mahley R. W., Agard D. A. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science. 1991 Jun 28;252(5014):1817–1822. doi: 10.1126/science.2063194. [DOI] [PubMed] [Google Scholar]
  42. Wurtman R. J. Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends Neurosci. 1992 Apr;15(4):117–122. doi: 10.1016/0166-2236(92)90351-8. [DOI] [PubMed] [Google Scholar]
  43. de Ruiter J. P., Uylings H. B. Morphometric and dendritic analysis of fascia dentata granule cells in human aging and senile dementia. Brain Res. 1987 Feb 3;402(2):217–229. doi: 10.1016/0006-8993(87)90028-x. [DOI] [PubMed] [Google Scholar]
  44. van Duijn C. M., de Knijff P., Cruts M., Wehnert A., Havekes L. M., Hofman A., Van Broeckhoven C. Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease. Nat Genet. 1994 May;7(1):74–78. doi: 10.1038/ng0594-74. [DOI] [PubMed] [Google Scholar]

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