Acta Neuropathologica

, Volume 111, Issue 1, pp 15–20 | Cite as

A 3’-UTR polymorphism in the oxidized LDL receptor 1 gene increases Aβ40 load as cerebral amyloid angiopathy in Alzheimer’s disease

  • Jing Shi
  • Jinzhou Tian
  • Antonia Pritchard
  • Corinne Lendon
  • Jean-Charles Lambert
  • Takeshi Iwatsubo
  • David M. A. Mann
Regular Paper


It is presently unclear whether polymorphic variations in the oxidized low-density lipoprotein receptor 1 (OLR1), or low-density lipoprotein receptor-related protein 1 (LRP1), genes act as risk factors for Alzheimer’s disease (AD). In the present study, we have investigated the extent of amyloid β protein (Aβ) deposition as cerebral amyloid angiopathy (CAA) or senile plaques (SP) in relationship to OLR1 +1071 and +1073 polymorphisms and LRP1 C766T polymorphism in patients with AD There was an increased Aβ40 load as CAA, but not as SP, in frontal cortex of AD patients carrying OLR1+1073 CC genotype, compared to those with CT, TT or CT+TT genotypes, but only in those individuals without apolipoprotein (APOE) ε4 allele. No differences in total Aβ or Aβ42 load as CAA or SP between OLR1+1073 genotypes was seen, nor were there any differences between OLR1+1071 and LRP1 genotypes for any measure of Aβ. Present data suggests that homozygosity for the C allele for OLR1+1073 polymorphism, selectively in individuals without APOE ε4 allele, may impair clearance of Aβ, and particularly Aβ40, from the brain across the blood-brain barrier, leading to its ‘diversion’ into perivascular drainage channels, thereby increasing the severity of CAA in such persons.


Alzheimer’s disease OLR1 gene LRP1 gene Cerebral amyloid angiopathy Amyloid β protein 


  1. 1.
    Bertram L, Parkinson M, Mullin K, Menon R, Blacker D, Tanzi RE (2004) No association between a previously reported OLR1 3’ UTR polymorphism and Alzheimer’s disease in a large family sample. J Med Genet 41:286–288CrossRefPubMedGoogle Scholar
  2. 2.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRefGoogle Scholar
  3. 3.
    D’Introno A, Solfrizzi V, Colacicco AM, Capurso C, Torres F, Capurso SA, Capurso A, Panza F (2005) Polymorphisms in the oxidized low-density lipoprotein receptor-1 gene and risk of Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 60:280–284PubMedGoogle Scholar
  4. 4.
    Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890CrossRefPubMedGoogle Scholar
  5. 5.
    Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322–325CrossRefPubMedGoogle Scholar
  6. 6.
    Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185PubMedGoogle Scholar
  7. 7.
    Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Sturchler-Pierrat C, Burki K, et al (2004) Aβ is targeted to the vasculature in a mouse model of hereditary cerebral haemorrhage with amyloidosis. Nat Neurosci 7:954–960CrossRefPubMedGoogle Scholar
  8. 8.
    Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13:45–53CrossRefPubMedGoogle Scholar
  9. 9.
    Kamboh MI (2004) Molecular genetics of late onset Alzheimer’s disease. Ann Hum Genet 68:381–404CrossRefPubMedGoogle Scholar
  10. 10.
    Kehoe P, Wavrant-De Vrieze F, Crook R, Wu WS, Holmans P, Fenton I, Spurlock G, Norton N, Williams H, Williams N, et al (1999) A full genome scan for late onset Alzheimer’s disease. Hum Mol Genet 8:237–245CrossRefPubMedGoogle Scholar
  11. 11.
    Keller JN, Hanni KB, Markesbery WR (1999) Oxidized low-density lipoprotein induces neuronal death: implications for calcium, reactive oxygen species, and caspases. J Neurochem 72:2601–2609CrossRefPubMedGoogle Scholar
  12. 12.
    Keller JN, Hanni KB, Kindy M (2000) Oxidized high-density lipoprotein induces neuron death. Exp Neurol 161:621–630CrossRefPubMedGoogle Scholar
  13. 13.
    Ladu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, Getz G (2000) Lipoproteins in the central nervous system. Ann NY Acad Sci 903:167–175PubMedGoogle Scholar
  14. 14.
    Lambert JC, Luedecking-Zimmer E, Merrot S, Hayes A, Thaker U, Desai P, Houzet A, Hermant X, Cottel D, Pritchard A, et al (2003) Association of 3’-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer’s disease. J Med Genet 40:424–430CrossRefPubMedGoogle Scholar
  15. 15.
    Luedecking-Zimmer E, Dekosky ST, Chen Q, Barmada MM, Kamboh MI (2002) Investigation of oxidized LDL-receptor 1(OLR1) as the candidate gene for Alzheimer’s disease on chromosome 12. Hum Genet 111:443–451CrossRefPubMedGoogle Scholar
  16. 16.
    Mann DMA, Iwatsubo T, Ihara Y, Cairns NJ, Lantos PL, Bogdanovic N, Lannfelt L, Winblad B, Maat-Schieman MLC, Rossor MN (1996) Predominant deposition of amyloid β42(43) in plaques in cases of Alzheimer’s disease and hereditary cerebral haemorrhage associated with mutations in the amyloid precursor protein gene. Am J Pathol 148:1257–1266PubMedGoogle Scholar
  17. 17.
    Mann DMA, Iwatsubo T, Pickering-Brown SM, Owen F, Saido TC, Perry RH (1997) Preferential deposition of amyloid β protein (Aβ) in the form Aβ40 in Alzheimer’s disease is associated with a gene dosage effect of the apolipoprotein E E4 allele. Neurosci Lett 221:81–84CrossRefPubMedGoogle Scholar
  18. 18.
    Mann DMA, Pickering-Brown S, Baba M, Iwatsubo T (2001) Amyloid angiopathy and variability in Aβ deposition in PS-1 linked Alzheimer’s disease. Am J Pathol 158:2165–2175PubMedGoogle Scholar
  19. 19.
    Mayeux R, Lee JH, Romas SN, Mayo D, Santana V, Williamson J, Ciappa A, Rondon HZ, Estevez P, Lantigua R, et al (2002) Chromosome-12 mapping of late-onset Alzheimer disease among Caribbean Hispanics. Am J Hum Genet 70:237–243CrossRefPubMedGoogle Scholar
  20. 20.
    Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, Belle G van, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  21. 21.
    Myers A, Wavrant De-Vrieze F, Holmans P, Hamshere M, Crook R, Compton D, Marshall H, Meyer D, Shears S, Booth J, et al (2002) Full genome screen for Alzheimer disease: stage II analysis. Am J Med Genet 114:235–244CrossRefPubMedGoogle Scholar
  22. 22.
    Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO (2003) Capillary and arterial cerebral amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29:106–117CrossRefPubMedGoogle Scholar
  23. 23.
    Pritchard A, St Clair D, Lemmon H, Mann DMA, Lendon C (2004) No association between polymorphisms in the lectin-like oxidised low density lipoprotein receptor (OLR1) gene on chromosome 12 and Alzheimer’s disease in a UK cohort. Neurosci Lett 366:126–129CrossRefPubMedGoogle Scholar
  24. 24.
    Pritchard A, Harris J, Pritchard CW, St Clair D, Lemmon H, Lambert JC, Chartier-Harlin MC, Hayes A, Thaker U, Iwatsubo T, et al (2005) Association study and meta-analysis of low density lipoprotein receptor related protein in Alzheimer’s disease. Neurosci Lett 382:221–226CrossRefPubMedGoogle Scholar
  25. 25.
    Rogaeva E, Premkumar S, Song Y, Sorbi S, Brindle N, Paterson A, Duara R, Levesque G, Yu G, Nishimura M, et al (1998) Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. JAMA 280:614–618CrossRefPubMedGoogle Scholar
  26. 26.
    Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S (1995) Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 14:457–466CrossRefPubMedGoogle Scholar
  27. 27.
    Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, et al (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2:864–870CrossRefPubMedGoogle Scholar
  28. 28.
    Schippling S, Kontush A, Arlt S, Buhmann C, Sturenburg HJ, Mann U, Muller-Thomsen T, Beisiegel U (2000) Increased lipoprotein oxidation in Alzheimer’s disease. Free Radic Biol Med 28:351–360CrossRefPubMedGoogle Scholar
  29. 29.
    Scott WK, Grubber JM, Conneally PM, Small GW, Hulette CM, Rosenberg CK, Saunders AM, Roses AD, Haines JL, Pericak-Vance MA (2000) Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet 66:922–932CrossRefPubMedGoogle Scholar
  30. 30.
    Seubert P, Oltersdorf T, Lee MG, Barbour R, Blomquist C, Davis DL (1993) Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature 361:260–263CrossRefPubMedGoogle Scholar
  31. 31.
    Tabner BJ, Turnbull S, El-Agnaf OM, Allsop D (2002) Formation of hydrogen peroxide and hydroxyl radicals from A(beta) and alpha-synuclein as a possible mechanism of cell death in Alzheimer’s disease and Parkinson’s disease. Free Radic Biol Med 32:1076–1083CrossRefPubMedGoogle Scholar
  32. 32.
    Tian J, Shi J, Bailey K, Mann DM (2003) Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer’s disease. Neurosci Lett 352:137–140CrossRefPubMedGoogle Scholar
  33. 33.
    Tian J, Shi J, Bailey K, Mann DM (2004) Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer’s disease. Neuropathol Appl Neurobiol 30:46–56CrossRefPubMedGoogle Scholar
  34. 34.
    Tian J, Shi J, Bailey K, Lendon CL, Pickering-Brown SM, Mann DMA (2004) Association of cerebral white matter loss, arteriosclerosis and cerebral amyloid angiopathy in Alzheimer’s disease with Apolipoprotein E genotype. J Neurol Neurosurg Psychiatry 75:696–699CrossRefPubMedGoogle Scholar
  35. 35.
    Ulery PG., Strickland DK (2000) LRP in Alzheimer’s disease: friend or foe? J Clin Invest 106:1077–1079PubMedGoogle Scholar
  36. 36.
    Weller RO, Massey A, Kuo YM, Roher AE (2000) Cerebral amyloid angiopathy: accumulation of A beta in interstitial fluid drainage pathways in Alzheimer’s disease. Ann NY Acad Sci 903:110–117PubMedGoogle Scholar
  37. 37.
    Wenham PR, Price WH, Blundell G (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet 337:1158–1159CrossRefGoogle Scholar
  38. 38.
    Wu WS, Holmans P, Wavrant-DeVrieze F, Shears S, Kehoe P, Crook R, Booth J, Williams N, Perez-Tur J, Roehl K, et al (1998) Genetic studies on chromosome 12 in late-onset Alzheimer disease. JAMA 280:619–622CrossRefPubMedGoogle Scholar
  39. 39.
    Yamanaka S, Zhang XY, Miura K, Kim S, Iwao H (1998) The human gene encoding the lectin-type oxidized LDL receptor (OLR1) is a novel member of the natural killer gene complex with a unique expression profile. Genomics 54:191–199CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Jing Shi
    • 1
    • 2
  • Jinzhou Tian
    • 1
    • 2
  • Antonia Pritchard
    • 3
  • Corinne Lendon
    • 3
  • Jean-Charles Lambert
    • 4
  • Takeshi Iwatsubo
    • 5
  • David M. A. Mann
    • 1
  1. 1.Clinical Neuroscience Research GroupUniversity of Manchester, Hope HospitalSalfordUK
  2. 2.Department of Care of the Elderly, Dongzhimen HospitalBeijing University of Chinese MedicineBeijingChina
  3. 3.Molecular Psychiatry, Queen Elizabeth Psychiatry HospitalUniversity of BirminghamBirminghamUK
  4. 4.INSERM 508Institut Pasteur de LilleLilleFrance
  5. 5.Department of NeuropathologyUniversity of TokyoTokyoJapan

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