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Journal of Molecular Neuroscience

, Volume 23, Issue 3, pp 247–254 | Cite as

In vivo effects of apoE and clusterin on amyloid-β metabolism and neuropathology

  • David M. HoltzmanEmail author
Original Article

Abstract

The ε4 allele of apolipoprotein E APOE is a risk factor for Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), and the ε2 allele is associated with a decreased risk for AD. There is strong evidence to suggest that a major, if not the main, mechanism underlying the link between apoE and both AD and CAA is related to the ability of apoE to interact with the amyloid-β (Aβ) peptide and influence its clearance, aggregation, and conformation. In addition to a number of in vitro studies supporting this concept, in vivo studies with amyloid precursor protein (APP) transgenic mice indicate that apoE and a related molecule, clusterin (also called apolipoprotein J), have profound effects on the onset of Aβ deposition, as well as the local toxicity associated with Aβ deposits both in the brain parenchyma and in cerebral blood vessels. Taken together, these studies suggest that altering the expression of apoE and clusterin in the brain or the interactions between these molecules and Aβ would alter AD pathogenesis and provide new therapeutic avenues for prevention or treatment of CAA and AD.

Index Entries

Alzheimer’s disease apolipoprotein E clusterin amyloid 

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References

  1. Bales K. R., Verina T., Cummins D. J., Du Y., Dodel J. C., Saura J., et al. (1999) Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 96, 15233–15238.PubMedCrossRefGoogle Scholar
  2. Bales K. R., Verina T., Dodel R. C., Du Y., Altstiel L., Bender M., et al. (1997) Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat. Genet. 17, 263–264.PubMedCrossRefGoogle Scholar
  3. Biere A. L., Ostaszewski B., Zhao H., Gillespie S., Younkin S. G., and Selkoe D. J. (1995) Co-expression of β-amyloid precursor protein (βAPP) and apolipoprotein E in cell culture: analysis of βAPP processing. Neurobiol. Dis. 2, 177–187.PubMedCrossRefGoogle Scholar
  4. Brendza R. P., O’Brien C., Simmons K., McKeel D. W., Bales K. R., Paul S. M., et al. (2003) PDAPP;YFP double transgenic mice: a tool to study amyloid-β associated changes in axonal, dendritic, and synaptic structure. J. Comp. Neurol. 456, 375–383.PubMedCrossRefGoogle Scholar
  5. Calero M., Rostagno A., Matsubara E., Zlokovic B., Frangione B., and Ghiso J. (2000) Apolipoprotein J (clusterin) and Alzheimer’s disease. Microsc. Res. Tech. 50, 305–315.PubMedCrossRefGoogle Scholar
  6. Calhoun M. E., Burgermeister P., Phinney A. L., Stalder M., Tolnay M., Wiederhold K.- H., et al. (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc. Natl. Acad. Sci. USA 96, 14088–14093.PubMedCrossRefGoogle Scholar
  7. Castano E. M., Prelli F., Wisniewski T., Golabek A., Kumar R. A., Soto C., et al. (1995) Fibrillogenesis in Alzheimer’s disease of amyloid beta peptides and apolipoprotein E. Biochem. J. 306, 599–604.PubMedGoogle Scholar
  8. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923.PubMedCrossRefGoogle Scholar
  9. Davis J. and Van Nostrand W. E. (1996) Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein. Proc. Natl. Acad. Sci. USA 93, 2996–3000.PubMedCrossRefGoogle Scholar
  10. DeMattos R. B., Brendza R. P., Heuser J. E., Kierson M., Cirrito J. R., Fryer J. D., et al. (2001) Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice. Neurochem. Int. 39, 415–425.PubMedCrossRefGoogle Scholar
  11. DeMattos R. B., O’dell M. A., Parsadanian M., Taylor J. W., Harmony J. A. K., Bales K. R., et al. (2002a) Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 99, 10843–10848.PubMedCrossRefGoogle Scholar
  12. DeMattos R. B., Cirrito J. R., Parsadanian M., May P. C., O’Dell M. A., Taylor J. W., et al. (2004) ApoE and clusterin cooperatively suppress Aβ levels and deposition: Evidence that apoE regulates extracellular Aβ metabolism in vivo. Neuron 41, 193–202.PubMedCrossRefGoogle Scholar
  13. DeMattos R. B., Parsadanian M., O’Dell M. A., Taylor J. W., Bales K. R., Paul S. M., et al. (2002b) Apolipoprotein E3 dose dependent modulation of Aβ deposition in a transgenic mouse model of Alzheimer’s disease. Soc. Neurosci. Abstr. 32, 723.Google Scholar
  14. Fagan A. M., Holtzman D. M., Munson G., Mathur T., Schneider D., Chang L. K., et al. (1999) Unique lipoproteins secreted by primary astrocytes from wild type, apoE (-/-) and human apoE transgenic mice. J. Biol. Chem. 274, 30001–30007.PubMedCrossRefGoogle Scholar
  15. Fagan A. M., Watson M., Parsadanian M., Bales K. R., Paul S. M., and Holtzman D. M. (2002) Human and murine apoE markedly influence Aβ metabolism both prior and subsequent to plaque formation in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 9, 305–318.PubMedCrossRefGoogle Scholar
  16. Fryer J. D., Taylor J. W., DeMattos R. B., Bales K. R., Paul S. M., Parsadanian M., and Holtzman D. M. (2003) Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in APP transgenic mice. J. Neurosci. 23, 7889–7896.PubMedGoogle Scholar
  17. Games D., Adams D., Alessandrini R., Barbour R., Berthelette P., Blackwell C., et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527.PubMedCrossRefGoogle Scholar
  18. Ghiso J., Matsubara E., Koudinov A., Choi-Miura N. H., Tomita M., Wisniewski T., et al. (1993) The cerebrospinal-fluid form of Alzheimer’s amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. Biochem. J. 293, 27–30.PubMedGoogle Scholar
  19. Goate A., Chartier-Harlon M. C., Mullan M., Brown J., Crawford F., Fidani L., et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706.PubMedCrossRefGoogle Scholar
  20. Golde T. E., Eckman C. B., and Younkin S. G. (2000) Biochemical detection of Aβ isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer’s disease. Biochim. Biophys. Acta 1502, 172–187.PubMedGoogle Scholar
  21. Gomez-Isla T., Price J. L., McKeel D. W., Morris J., C., Growdon J. H., and Hyman B. T. (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J. Neurosci. 16, 4491–4500.PubMedGoogle Scholar
  22. Greenberg S. M., Rebeck G. W., Vonsattel J. P. G., Gomez-Isla T., and Hyman B. T. (1995) Apolipoprotein E ε4 and cerebral hemorrhage associated with amyloid angiopathy. Ann. Neurol. 38, 254–259.PubMedCrossRefGoogle Scholar
  23. Holtzman D. M. (2001) Role of apoE/Aβ interactions in the pathogenesis of Alzheimer’s disease and cerebral amyloid angiopathy. J. Mol. Neurosci. 17, 147–155.PubMedCrossRefGoogle Scholar
  24. Holtzman D. M., Bales K. R., Tenkova T., Fagan A. M., Parsadanian M., Sartorius L. J., et al. (2000a) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 97, 2892–2897.PubMedCrossRefGoogle Scholar
  25. Holtzman D. M., Bales K. R., Wu S., Bhat P., Parsadanian M., Fagan A. M., et al. (1999) In vivo expression of apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimers disease. J. Clin. Invest. 103, R15-R21.PubMedGoogle Scholar
  26. Holtzman D. M., Fagan A. M., Mackey B., Tenkova T., Sartorius L., Paul S. M., et al. (2000b) ApoE facilitates neuritic and cerebrovascular plaque formation in the APPsw mouse model of Alzheimer’s disease. Ann. Neurol. 47, 739–747.PubMedCrossRefGoogle Scholar
  27. Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., Youkin S., et al. (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102.PubMedCrossRefGoogle Scholar
  28. Joachim C. L., Duffy L. K., Morris J. H., and Selkoe D. J. (1988) Protein chemical and immunocytochemical studies of meningovascular β-amyloid protein in Alzheimer’s disease and normal aging. Brain Res. 474, 100–111.PubMedCrossRefGoogle Scholar
  29. Kindy M. S. and Rader D. J. (1998) Reduction in amyloid A formation in apolipoprotein-E-deficient mice. Am. J. Pathol. 152, 1387–1395.PubMedGoogle Scholar
  30. LaDu M. J., Falduto M. T., Manelli A. M., Reardon C. A., Getz G. S., and Frail D. E. (1994) Isoform-specific binding of apolipoprotein E to β-amyloid. J. Biol. Chem. 269, 23404–23406.Google Scholar
  31. LaDu M. J., Gilligan S. M., Lukens S. R., Cabana V. G., Reardon C. A., Van Eldik L. J., et al. (1998) Nascent astrocyte particles differ from lipoproteins in CSF. J. Neurochem. 70, 2070–2081.PubMedCrossRefGoogle Scholar
  32. Lai F. and Williams R. S. (1989) A prospective study of Alzheimer disease in Down syndrome. Arch. Neurol. 46, 849–853.PubMedGoogle Scholar
  33. Lambert M. P., Barlow A. K., Chromy B. A., Edwards C., Freed R., Liosatsos M., et al. (1998) Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95, 6448–6453.PubMedCrossRefGoogle Scholar
  34. Levy E., Carman M. D., Fernandez-Madrid I., et al. (1990) Mutation of the Alzheimer’s beta-protein gene in amyloid of hereditary cerebral hemorrhage. Science 248, 1124–1126.PubMedCrossRefGoogle Scholar
  35. Ma J., Yee A., Brewer H. B., Das S., and Potter H. (1994) Amyloid-associated proteins alpha-1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372, 92–94.PubMedCrossRefGoogle Scholar
  36. Matsubara E., Frangione B., and Ghiso J. (1995) Characterization of apolipoprotein J-Alzheimer’s Aβ interaction. J. Biol. Chem. 270, 7563–7567.PubMedCrossRefGoogle Scholar
  37. Matsubara E., Soto C., Governale S., Frangione B., and Ghiso J. (1996) Apolipoprotein J and Alzheimer’s amyloid beta solubility. Biochem. J. 316, 671–679.PubMedGoogle Scholar
  38. May P. C. and Finch C. E. (1992) Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration. Trends Neurol. Sci. 15, 391–396.CrossRefGoogle Scholar
  39. May P. C., Lampert-Etchells M., Johnson S. A., Poirier J., Masters J. N., and Finch C. E. (1990) Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer’s disease and in response to experimental lesions in rat. Neuron 5, 831–839.PubMedCrossRefGoogle Scholar
  40. Morris J. C. and Price J. L. (2001) Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J. Mol. Neurosci. 17, 101–118.PubMedCrossRefGoogle Scholar
  41. Mullan M., Crawford F., Axelman K., Houlden H., Lilius L., Winblad B., et al. (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nat. Genet. 1, 345–347.PubMedCrossRefGoogle Scholar
  42. Nilsberth C., Westlind-Danielsson A., Eckman C. B., Condron M. M., Axelman K., Forsell C., et al. (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Aβ protofibril formation. Nat. Neurosci. 4, 887–893.PubMedCrossRefGoogle Scholar
  43. Oda T., Wals P., Osterburg H. H., Johnson S. A., Pasinetti G. M., Morgan T. M., et al. (1995) Clusterin (apoJ) alters the aggregation of amyloid β-peptide (Aβ1-42) and forms slowly sedimenting Aβ complexes that cause oxidative stress. Exp. Neurol. 136, 22–31.PubMedCrossRefGoogle Scholar
  44. Price J. L. and Morris J. C. (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann. Neurol. 45, 358–368.PubMedCrossRefGoogle Scholar
  45. Price J. L., Ko A. I., Wade M. J., Tsou S. K., McKeel D. W., and Morris J. C. (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer Disease. Arch. Neurol. 58, 1395–1402.PubMedCrossRefGoogle Scholar
  46. Roheim P. S., Carey M., Forte T., and Vega G. L. (1979) Apolipoproteins in human cerebrospinal fluid. Proc. Natl. Acad. Sci. USA 76, 4646–4649.PubMedCrossRefGoogle Scholar
  47. Rumble B., Retalack R., Hilbich C., Simms G., Multhaup G., Martins R., et al. (1989) Amyloid A4 protein and its precursors in Down’s syndrome and Alzheimer’s disease. N. Engl. J. Med. 320, 1446–1452.PubMedCrossRefGoogle Scholar
  48. Sanan D. A., Weisgraber K. H., Russel S. J., Mahley R. W., Huang D., Saunders A., et al. (1994) Apolipoprotein E associates with β amyloid peptide of Alzheimer’s disease to form novel monofibrils. J. Clin. Invest. 94, 860–869.PubMedCrossRefGoogle Scholar
  49. Strittmatter W. J. and Roses A. D. (1996) Apolipoprotein E and Alzheimer’s disease. Annu. Rev. Neurosci. 19, 53–77.PubMedCrossRefGoogle Scholar
  50. Strittmatter W. J., Saunders A. M., Schmechel D., Pericak-Vance M., Enghild J., Salvesen G. S., et al. (1993) Apolipoprotein E: high avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981.PubMedCrossRefGoogle Scholar
  51. Sullivan P. M., Mezdour H., Aratani Y., Knouff C., Najib J., Reddick R. L., et al. (1997) Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J. Biol. Chem. 272, 17972–17980.PubMedCrossRefGoogle Scholar
  52. Suzuki N., Cheung T. T., Cai X. D., Odaka A., Otvos L. J., Eckman C., et al. (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264, 1336–1340.PubMedCrossRefGoogle Scholar
  53. Vinters H. V. (1987) Cerebral amyloid angiopathy: A critical review. Stroke 18, 311–324.PubMedGoogle Scholar
  54. Wisniewski K. E., Wisniewski H. M., and Wen G. Y. (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann. Neurol. 17, 278–282.PubMedCrossRefGoogle Scholar
  55. Yamaguchi H., Sugihara S., Ogawa A., Oshima N., and Ihara Y. (2001) Alzheimer beta amyloid deposition enhanced by ApoE epsilon 4 gene precedes neurofibrillary pathology in the frontal association cortex of nondemented senior subjects. J. Neuropathol. Exp. Neurol. 60, 731–739.PubMedGoogle Scholar
  56. Zlokovic B. V., Martel C. L., Mackic J. B., Matsubara E., Wisniewski T., McComb J. G., et al. (1994) Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer’s amyloid β. Biochem. Biophys. Res. Commun. 205, 1431–1437.PubMedCrossRefGoogle Scholar
  57. Zlokovic B. V., Martel C. L., Matsubara E., McComb J. G., Zheng G., McCluskey R. T., et al. (1996) Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer’s disease amyloid β at the blood-brain and blood-cerebrospinal fluid barriers. Proc. Natl. Acad. Sci. USA 93, 4229–4234.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  1. 1.Center for the Study of Nervous System Injury, Alzheimer’s Disease Research Center, Departments of Neurology, and Molecular Biology and PharmacologyWashington University School of MedicineSt. Louis

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