Skip to main content
NCBI home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;5(3):254–266. doi: 10.1111/j.1582-4934.2001.tb00159.x

Apolipoprotein E: a major piece in the Alzheimer's disease puzzle

A Cedazo‐Mínguez 1,✉, R F Cowburn 1
PMCID: PMC6514775  PMID: 12067484

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple etiologies. The presence of the E4 isoform of apolipoprotein E (apoE) has been shown to increase the risk and to decrease the age of onset for AD and is the major susceptibility factor known for the disease. ApoE4 has been shown to intensify all the biochemical distrubances characteristic of AD, including beta amyloid (Aβ) deposition, tangle formation, neuronal cell death, oxidative stress, synaptic plasticity and dysfunctions of lipid homeostasis and cholinergic signalling. In contrast, other apoE isoforms are protective. Here we review and discuss these major hypotheses of the apoE4‐AD association.

Keywords: Alzheimer's disease, apolipoprotein E, amyloid, cell signalling, oxidative stress, synaptic plasticity

References

  • 1. Selkoe D.J., Alzheimer's Disease: Genes, Proteins and Therapy, Phys. Rev., 81: 741–766, 2001. [DOI] [PubMed] [Google Scholar]
  • 2. Kehoe P., Wavrant‐De Vrieze. F , Crook R., Wu W.S., Holmans P., Fenton I., Spurlock G., Norton N., Williams H., Williams N., Lovestone S., PerezTur J., Hutton M., Chartier‐Harlin M.C., Shears S., Roehl K., Booth J., Van Voorst W., Ramic D., Williams J., Goate A., Hardy J., Owen M.J., A full genome scan for late onset Alzheimer's disease, Hum. Mol. Genet., 8: 237–45, 1999. [DOI] [PubMed] [Google Scholar]
  • 3. Beffert U., Danik M., Krzykowski P., Ramassamy C., Berrada F., Poirier J., The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease, Brain Res. Rev., 27: 119–142, 1998. [DOI] [PubMed] [Google Scholar]
  • 4. Weisgraber K.H. and Mahley R.W., Human apolipoprotein E: the Alzheimer's Disease connection, FASEB J., 10: 1485–1494, 1996. [DOI] [PubMed] [Google Scholar]
  • 5. Baskin F., Smith G.M., Fosmire J.A., Rosenberg R.N., Altered apolipoprotein E secretion in cytokine treated human astrocyte cultures, J. Neurol. Sci., 148: 15–8, 1997. [DOI] [PubMed] [Google Scholar]
  • 6. Stone D.J., Rozovsky L., Morgan T.E., Anderson C.P., Hajian H., Finch C.E., Astrocytes and microglia respond to estrogen with increased apoE mRNA in vitro, Exp. Neurol., 143: 313–8, 1997. [DOI] [PubMed] [Google Scholar]
  • 7. Cedazo‐Minguez A., Hamker U., Veh H., Meske V., Albert F., Cowburn R.F., Ohm T.G., Regulation of apolipoprotein E secretion in rat primary hippocampal astrocyte cultures, Neuroscience, 105: 651–661, 2001. [DOI] [PubMed] [Google Scholar]
  • 8. Forstner M., Peters‐Libeu C., Contreras‐Forrest E., Newhouse Y., Knapp M., Rupp B., Weisgraber K. H., Carboxyl‐terminal domain of human apolipo‐protein E: expression, purification, and crystallization, Protein Expr. Purif., 17: 267–272, 1999. [DOI] [PubMed] [Google Scholar]
  • 9. Smith J.D., Apolipoprotein E4: an allele associated with many disease, Ann Med., 32: 118–127, 2000. [DOI] [PubMed] [Google Scholar]
  • 10. Pericak‐Vance M.A., Bebout J.L., Gaskell P.C. Jr., Yamaoka L.H., Hung W.Y., Alberts M.J., Walker A.P., Bartlett R.J., Haynes C.A., Welsh K.A., Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage, Am. J. Hum. Genet., 48: 1034–50, 1991. [PMC free article] [PubMed] [Google Scholar]
  • 11. 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, 261: 921–923, 1993. [DOI] [PubMed] [Google Scholar]
  • 12. Rubinsztein D.C, Easton D.F., Apolipoprotein E genetic variation and Alzheimer's disease. A meta‐analysis, Dement. Geriatr. Cogn. Disord., 10: 199–209, 1999. [DOI] [PubMed] [Google Scholar]
  • 13. Bullido M.J., Artiga M.J., Recuero M., Sastre I., Garci M.A., Aldudo J., Lendon C, Han S.W., Morris J.C., Frank A., Vazquez J., Goate A., Region of APOE associated with risk for Alzheimer's dementia, Nat, Genet., 18: 69–71, 1998. [DOI] [PubMed] [Google Scholar]
  • 14. Lambert J.C., Pasquier F., Cottel D., Frigard B., Amouyel P., Chartier‐Harlin M.C. A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease, Hum. Mol. Genet., 7: 533–40, 1998. [DOI] [PubMed] [Google Scholar]
  • 15. Namba Y., Tomonaga M., Kawasaki H., Otomo E., Ikeda K., Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt‐Jakob disease, Brain Res., 541: 163–6, 1991. [DOI] [PubMed] [Google Scholar]
  • 16. Wisniewski T., Frangione B., Apolipoprotein E: a patohological chaperone protein with cerebral and systemic amyloid, Neurosci Lett., 135: 235–238, 1992. [DOI] [PubMed] [Google Scholar]
  • 17. Strittmatter W.J., Saunders A.M., Schmechel D., Pericak‐Vance M., Enghild J., Salvesen G.S., Roses A.D., Apolipoprotein E: high‐avidity binding to β‐myloid and increased frequency of type 4 allele in late‐onset familial Alzheimer's disease, Proc. Natl. Acad Sci USA, 90: 1977–1981, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Permanne B, Perez C., Soto C., Frangione B., and Wisniewski T., Detection of apolipoprotein E/dimeric soluble amyloid beta complexes in Alzheimer's disease brain supernatants, Biochem. Biophys. Res. Commun., 270: 715–720, 1997. [DOI] [PubMed] [Google Scholar]
  • 19. Wisniewski T., Castaño E., Golabek A., Vogel T., Fragione B., Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro, Am. J. Pathol., 145: 1030–1035, 1994. [PMC free article] [PubMed] [Google Scholar]
  • 20. Bales K.R., Verina T., Cummins D.J., Du Y., Dodel R.C., Saura J., Fishman C.E., DeLong C.A., Piccardo P., Petegnief V., Ghetti B., Paul S.M., Apolipoprotein E is essential for amyloid deposition in the APP (V71F) transgenic mouse model of Alzheimer's disease, Proc. Nat. Acad. Sci. USA, 96: 5233–8, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. LaDu, M.J. , Falduto, M.T. , Manelli, A.M. , Reardon, C.A. , Getz, G.S. , Frail, D.E. , Isoformspecific binding of apolipoprotein E to betaamyloid, J. Biol. Chem., 269: 23403–23406, 1994. [PubMed] [Google Scholar]
  • 22. Holtzman D.M., Bales K.R., Wu S., Bhat P., Parsadanian M., Fagan A.M., Chang L.K., Sun Y., Paul S.M., Expression of human apolipoprotein E reduces amyloid‐beta deposition in a mouse model of Alzheimer's disease, J. Clin. Invest., 103: R15–R21, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Kuo Y.M., Crawford F., Mullan M., Kokjohn T.A., Emmerling M.R., Weller R.O., Roher A.E., Elevated A beta and apolipoprotein E in A betaPP transgenic mice and its relationship to amyloid accumulation in Alzheimer's disease, Mol. Med., 6: 430–9, 2000. [PMC free article] [PubMed] [Google Scholar]
  • 24. Buée L., Bussiere T., Buée‐Scherrer V., Delacourte A., Hof P.R., Tau protein isoforms, phosphorylation and role in neurodegenerative disorders, Brain Res. Rev., 33: 95–130, 2000. [DOI] [PubMed] [Google Scholar]
  • 25. 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., Han S.H., Hulette C., Einstein G., Schmechel D., Pericak‐Vance M.A., Roses A.D., Hypothesis: microtubule instability and paired helical filament formation in the Alzheimers disease brain are related to apolipoprotein E genotype, Exp. Neurol., 125: 163–171, 1994. [DOI] [PubMed] [Google Scholar]
  • 26. DeMattos R.B., Curtiss L.K., Williams D.L., A minimally lipidated form of cell‐derived apolipoprotein E exhibits isoform‐specific stimulation of neurite outgrowth in the absence of exogenous lipids or lipoproteins, J. Biol. Chem., 273: 4206–4212, 1998. [DOI] [PubMed] [Google Scholar]
  • 27. Genis I., Fisher A., Michaelson D.M., Site‐specific dephosphorylation of tau of apolipoprotein E‐deficient and control mice by M1 muscarinic agonist treatment, J. Neurochem., 72: 206–13, 1999. [DOI] [PubMed] [Google Scholar]
  • 28. Tesseur I, Van Dorpe J, Spittaels K, Van den Haute C, Moechars D, Van Leuven F., Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice, Am. J. Pathol., 156: 951–64, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Lovestone S., Anderton B.H., Hartley C., Jensen T.G., Jorgensen A.L., The intracellular Fate of apolipoprotein E is tau dependent and apoE allele specific, NeuroReport, 7: 1005–1008, 1996. [DOI] [PubMed] [Google Scholar]
  • 30. DeMattos R.B., Thorngate F.E., Williams D.L., A test of the cytosolic apolipoprotein E hypothesis fails to detect the escape of apolipoprotein E from the endocytic pathway into the cytosol and shows that direct expression of apolipoprotein E in the cytosol is cytotoxic, J. Neurosci., 19: 2464–73, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Muller W., Meske V., Berlin K., Scharnagl H., Marz W., Ohm T.G., Apolipoprotin E isoforms increase intracellular Ca2+ differentially through a omega‐agatoxin IVa‐sensitive Ca2+‐channel, Brain Pathol., 8: 641–653, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Wang X., Luebbe P., Gruenstein E., Zemlan, F. , Apolipoprotein E (ApoE) peptide regulates tau phosphorylation via two different signaling pathways, J. Neurosci. Res., 51: 658–665, 1998. [DOI] [PubMed] [Google Scholar]
  • 33. Kampers T., Pangalos M., Geerts H., Wiech H., Mandelkow, E. , Assembly of paired helical filaments from mouse tau: implications for the neurofibrillary pathology in transgenic mouse models for Alzhemer'sdisease, FEBS Lett., 451: 39–44, 1999. [DOI] [PubMed] [Google Scholar]
  • 34. Cedazo‐Mínguez A., Wiehager B., Huettinger M., Winblad B., Cowburn R.F., Effects of apolipoprotein E (apoE) isoforms, β‐amyloid (Aβ) (1–42), and apoE/Aβ complexes on Protein Kinase C‐α (PKC‐α) translocation and amyloid precursor protein (APP) processing in human SH‐SY5Y neuroblastoma cells and fibroblasts, Neurochem. Int., 38: 615–625, 2001. [DOI] [PubMed] [Google Scholar]
  • 35. Pei J‐J., Braak E., Braak H., Grundke‐Iqbal I., Iqbal, K. , Winblad B., Cowburn R.F., Distribution of active glycogen synthase kinase 3β (GSK‐3β) in brains staged for Alzheimer disease neurofibrillary changes, J. Neuropath. Exp. Neurol., 58: 1010–1019, 1999. [DOI] [PubMed] [Google Scholar]
  • 36. Gibb G., Pearce J., Betts J.C., Lovestone S., Hoffmann M.M., Maerz W., Blackstock W.P., Anderton, B.H. Differential effects of apolipoprotein E isoforms on phosphorylation at specific sites on tau by glycogen synthase kinase‐3βidentified by nano‐electrospray mass spectrometry, FEBS Lett., 485: 99–103, 2001. [DOI] [PubMed] [Google Scholar]
  • 37. Takashima A., Murayama M., Murayama O., Kohno T., Honda T., Yasutake K., Nihonmatsu N., Mercken M., Yamaguchi H., Sugihara S., Wolozin B., Presenilin 1 associates with glycogen synthase kinase‐3beta and its substrate tau, Proc. Natl. Acad. Sci. USA, 95: 9637–41, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Behrens J., von Kries J.P., Kuhl M., Bruhn L., Wedlich D., Grosschedl R., Birchmeier W., Functional interaction of beta‐catenin with the transcription factor LEF‐1, Nature, 382: 638–42, 1996. [DOI] [PubMed] [Google Scholar]
  • 39. Zhang Z., Hartmann H., Do V.M., Abramowski D., Sturchler‐Pierrat C., Staufenbiel M., Sommer B., van de Wetering M., Clevers H., Saftig P., De Strooper B., He X., Yankner B.A., Destabilization of beta‐catenin by mutations in presenilin‐1 potentiates neuronal apoptosis, Nature, 395: 698–702, 1998. [DOI] [PubMed] [Google Scholar]
  • 40. Ohkubo N., Mitsuda N., Tamatini M., Yamaguchi A., Lee Y‐D., Ogihara T., Vitek M.P., Tohyama, M. , Apolipoprotein E4 stimulates cAMP response element‐binding protein transcriptional activity through the extracellular kinase signal‐regulated kinase pathway, J. Biol. Chem., 276: 3046–3053, 2001. [DOI] [PubMed] [Google Scholar]
  • 41. Crutcher K.A., Clay M.A., Scott S.A, Tian X., Tolar M., Harmony J.A., Neurite degeneration elicited by apolipoprotein E peptides, Exp. Neurol., 130: 120–126, 1994. [DOI] [PubMed] [Google Scholar]
  • 42. Tolar M., Marques M., Harmony J., Crutcher K., Neurotoxicity of the 22 kDa thrombin‐cleavage fragment of apolipoprotein E related synthetic peptides is receptor mediated, J. Neurosci., 17: 5678–5686, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Montine K.S., Reich E., Neely M.D., Sidell K.R., Olson S.J., Markesbery W.R, Montine, T.J. , Distribution of reducible 4‐hydroxynonenal adduct immunoreactivity in Alzheimer disease is associated with APOE genotype, J. Neuropathol. Exp. Neurol., 57: 415–25, 1997. [DOI] [PubMed] [Google Scholar]
  • 44. Ramassamy C., Averill D., Beffert U., Theroux L., Lussier‐Cacan S., Cohn J. S., Christen Y., Schoofs A., Davignon J., Poirier, J. , Oxidative insults are associated with apolipoprotein E genotype in Alzheimer's disease brain, Neurobiol. Dis., 7: 23–37.2000. [DOI] [PubMed] [Google Scholar]
  • 45. Ma J., Brewer H.B. Jr., Potter H., Alzheimer A beta neurotoxicity: promotion by antichymotrypsin, ApoE4; inhibition by A beta‐related peptides, Neurobiol. Aging, 17: 773–80, 1996. [DOI] [PubMed] [Google Scholar]
  • 46. Whitson J.S., Mims M.P., Strittmatter W.J., Yamaki T., Morrisett J.D., Appel S.H., Attenuation of the neurotoxic effect of A beta amyloid peptide by apolipoprotein E, Biochem. Biophys. Res. Commun., 199: 163–70, 1994. [DOI] [PubMed] [Google Scholar]
  • 47. Miyata M. and Smith J.D. Apolipoprotein E allelespecific antioxidant activity and effects on cytotoxicity by oxidative insults and beta‐amyloid peptides, Nat. Genet., 14: 55–61, 1996. [DOI] [PubMed] [Google Scholar]
  • 48. Pedersen W.A., Chan S.L., Mattson M.P., A mechanism for the neuroprotective effect of apolipoprotein E: isoform‐specific modification by the lipid peroxidation product 4‐hydroxynonenal, J. Neurochem., 74: 1426–33, 2000. [DOI] [PubMed] [Google Scholar]
  • 49. Buttini M, Akeefe H, Lin C, Mahley R.W., Pitas R.E., Wyss‐Coray T., Mucke L., Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease, Neuroscience, 97: 207–10, 2000. [DOI] [PubMed] [Google Scholar]
  • 50. Hashimoto Y., Jiang H., Niikura T., Ito Y., Hagiwara A., Umezawa K., Abe Y., Mutuyama Y., Nishimoto I., Neuronal apoptosis by apolipoprotein E4 through low‐density lipopprotein receptorrelated protein and heterotrimeric GTPases, J. Neurosci., 15: 8401–8409, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Moulder K.L., Narita M., Chang L.K., Bu G., Johnson E.M. Jr., Analysis of a novel mechanism of neuronal toxicity produced by an apolipoprotein E‐derived peptide, J. Neurochem., 72: 1069–80, 1999. [DOI] [PubMed] [Google Scholar]
  • 52. Cedazo‐Mínguez A., Huettinger M., Cowburn R.F., Beta‐VLDL protects against Aβ(1–42) and apoE toxicity in human SH‐SY5Y neuroblastoma cells, NeuroReport, 12: 201–206, 2001. [DOI] [PubMed] [Google Scholar]
  • 53. Michikawa M., Fan Q.W., Isobe I., Yanagisawa K., Apolipoprotein E exhibits isoform‐specific promotion of lipid efflux from astrocytes and neurons in culture, J. Neurochem., 74: 1008–16, 2000. [DOI] [PubMed] [Google Scholar]
  • 54. Wolozin B., Kellman W., Ruosseau P., Celesia G.G., Siegel G., Decreased prevalence of Alzheimer disease associated with 3‐hydroxy‐3‐methyglutary1 coenzyme A inhibitors, Arch. Neurol., 57: 1439–43, 2000. [DOI] [PubMed] [Google Scholar]
  • 55. Fassbender K., Simons M., Bergmann C., Stroick M., Lutjohann D., Keller P., Runz H., Kuhl S., Bertsch T., von Bergmann, K. , Hennerici M., Beyreuther K., Hartmann T., Simvastatin strongly reduces levels of Alzheimer's disease beta ‐amyloid peptides Abeta 42 and Abeta40 in vitro and in vivo, Proc. Natl. Acad. Sci. USA, 98: 5856–61, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Poirier J., Apolipoprotein E and Alzheimer's disease. A role in amyloid catabolism, Ann. NY Acad. Sci., 924: 81–90, 2000. [DOI] [PubMed] [Google Scholar]
  • 57. Fan Q.W., Yu W., Senda T., Yanagisawa K., Michikawa M., Cholesterol‐dependent modulation of tau phosphorylation in cultured neurons, J. Neurochem., 76: 391–400, 2001. [DOI] [PubMed] [Google Scholar]
  • 58. Arendt T., Disturbance of neuronal plasticity is a critical pathogenetic event in Alzheimer's disease, Int. J. Dev. Neurosci., 19: 231–45, 2001. [DOI] [PubMed] [Google Scholar]
  • 59. 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, 264: 850–2, 1994. [DOI] [PubMed] [Google Scholar]
  • 60. Veinbergs I., Mallory M., Mante M., Rockenstein E., Gilbert J.R., Masliah E., Differntial neurotrophic effects of apolipoprotein E in aged transgenic mice, Neurosci. Lett., 265: 218–22, 1999. [DOI] [PubMed] [Google Scholar]
  • 61. Buttini M, Orth M, Bellosta S, Akeefe H, Pitas RE, Wyss‐Coray T, Mucke L, Mahley RW. Expression of human apolipoprotein E3 or E4 in the brains of Apoe −/− mice: isoform‐specific effects on neurodegeneration, J. Neurosci., 19: 4867–80, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Jope R.S., Song, L. , Powers R.E., Cholinergic activation of phosphoinositide signalling is impaired in Alzheimer's disease brain, Neurobio. Aging, 18: 111–120, 1997. [DOI] [PubMed] [Google Scholar]
  • 63. Ladner C.J., Celesia G.G., Magnuson D.J., Lee J.M., Regional alterations in M1 muscarinic receptor‐G protein coupling in Alzheimer's disease, J. Neuropathol. Exp. Neurol., 54: 783–9, 1995. [DOI] [PubMed] [Google Scholar]
  • 64. Poirier J., Delisle M‐C., Quirion R., Aubert I., Farlow M., Lahiri D., Hui S., Bertrand P.J. Nalbantoglu B., Gilfix M., Gauthier S., Apolipoprotein E allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer's disease, Proc Natl. Acad. Sci. USA, 92: 12260–12264, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Soininen H.O., Kosunen S., Helisalmi A., Mannermaa L., Paljarvi S., Talasniemi M., Ryynanen P., Riekkinen S., A severe loss of choline acetyltranferase in the frontal cortex of Alzheimer patients carrying apolipoprotein 4 allele, Neurosci. Lett., 187: 79–82, 1995. [DOI] [PubMed] [Google Scholar]
  • 66. Bronfman F.C., Tesseur I., Hofker M.H., Havekens L.M., Van Leuven F., No evidence for cholinergic problems in apolipoprotein E knockout and apolipoprotein E4 transgenic mice, Neuro-science, 93: 411–8, 2000. [DOI] [PubMed] [Google Scholar]
  • 67. Cedazo‐Mínguez A. and Cowburn R.F., Apolipoprotein E isoform‐specific disruption of phosphoinositide hydrolysis: protection by estrogen and glutathione, FEBS lett., In press. [DOI] [PubMed]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES