Skip to main content

Advertisement

SpringerLink
Log in

Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

The deposition of amyloid β-protein (Aβ) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer’s disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Aβ-deposits. In addition, as in Alzheimer’s disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) ε4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Aβ-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Aβ-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE ε4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the α2macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE ε4-associated subtype of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Agresti A (2002) Categorical data analysis, 2nd edn. Wiley, Hoboken

    Google Scholar 

  2. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders. American Psychiatric Association, Washington DC

  3. Attems J, Jellinger KA (2004) Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol (Berl) 107:83–90

    Article  Google Scholar 

  4. Attems J, Lauda F, Jellinger KA (2008) Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy: an autopsy study. J Neurol 255:70–76

    Article  PubMed  Google Scholar 

  5. Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM (1989) Tau and ubiquitin immunoreactivity at different stages of formation of Alzheimer neurofibrillary tangles. Prog Clin Biol Res 317:837–848

    CAS  PubMed  Google Scholar 

  6. Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118:103–113

    Article  CAS  PubMed  Google Scholar 

  7. Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE (2008) Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet 83:623–632

    Article  CAS  PubMed  Google Scholar 

  8. Bertram L, Tanzi RE (2008) Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9:768–778

    Article  CAS  PubMed  Google Scholar 

  9. Braak E, Braak H, Mandelkow EM (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87:554–567

    Article  CAS  PubMed  Google Scholar 

  10. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404

    Article  PubMed  Google Scholar 

  11. Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1:213–216

    Article  CAS  PubMed  Google Scholar 

  12. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  CAS  PubMed  Google Scholar 

  13. Braak H, Braak E (1998) Argyrophilic grain disease: frequency of occurrence in different age categories and neuropathological diagnostic criteria. J Neural Transm 105:801–819

    Article  CAS  PubMed  Google Scholar 

  14. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  15. Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA (2008) Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol 67:523–531

    Article  CAS  PubMed  Google Scholar 

  16. Christensen DZ, Schneider-Axmann T, Lucassen PJ, Bayer TA, Wirths O (2010) Accumulation of intraneuronal Abeta correlates with ApoE4 genotype. Acta Neuropathol 119:555–566

    Article  CAS  PubMed  Google Scholar 

  17. Christoforidis M, Schober R, Krohn K (2005) Genetic-morphologic association study: association between the low density lipoprotein-receptor related protein (LRP) and cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 31:11–19

    Article  CAS  PubMed  Google Scholar 

  18. Corder EH, Ghebremedhin E, Taylor MG, Thal DR, Ohm TG, 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

    Article  CAS  PubMed  Google Scholar 

  19. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  CAS  PubMed  Google Scholar 

  20. Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 118:4002–4013

    Article  CAS  PubMed  Google Scholar 

  21. Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105

    Article  CAS  PubMed  Google Scholar 

  22. Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD (1999) Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet 354:919–920

    Article  CAS  PubMed  Google Scholar 

  23. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278:1349–1356

    Article  CAS  PubMed  Google Scholar 

  24. Ghebremedhin E, Braak H, Braak E, Sahm J (1998) Improved method facilitates reliable APOE genotyping of genomic DNA extracted from formaldehyde-fixed pathology specimens. J Neurosci Methods 79:229–231

    Article  CAS  PubMed  Google Scholar 

  25. Ghebremedhin E, Schultz C, Thal DR, Del Tredici K, Rub U, Braak H (2002) Genetic association of argyrophilic grain disease with polymorphisms in alpha-2 macroglobulin and low-density lipoprotein receptor-related protein genes. Neuropathol Appl Neurobiol 28:308–313

    Article  CAS  PubMed  Google Scholar 

  26. Griffin WS, Liu L, Li Y, Mrak RE, Barger SW (2006) Interleukin-1 mediates Alzheimer and Lewy body pathologies. J Neuroinflammation 3:5

    Article  PubMed  Google Scholar 

  27. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 86:7611–7615

    Article  CAS  PubMed  Google Scholar 

  28. Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290

    Article  PubMed  Google Scholar 

  29. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917

    Article  CAS  PubMed  Google Scholar 

  30. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  PubMed  Google Scholar 

  31. Hartmann T, Kuchenbecker J, Grimm MO (2007) Alzheimer’s disease: the lipid connection. J Neurochem 103(Suppl 1):159–170

    Article  CAS  PubMed  Google Scholar 

  32. Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548

    CAS  PubMed  Google Scholar 

  33. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572

    Article  CAS  PubMed  Google Scholar 

  34. Hyman BT, Van Hoesen GW, Damasio AR (1987) Alzheimer’s disease: glutamate depletion in the hippocampal perforant pathway zone. Ann Neurol 22:37–40

    Article  CAS  PubMed  Google Scholar 

  35. Insausti R, Amaral DG (2004) Hippocampal Formation. In: Paxinos G, Mai JK (eds) The human nervous system. Elsevier, London, pp 872–914

    Google Scholar 

  36. Iqbal K, Braak H, Braak E, Grundke-Iqbal I (1993) Silver labeling of Alzheimer neurofibrillary changes and brain beta-amyloid. J Histotechnol 16:335–342

    Google Scholar 

  37. Jellinger KA, Attems J (2007) Neuropathological evaluation of mixed dementia. J Neurol Sci 257:80–87

    Article  CAS  PubMed  Google Scholar 

  38. Josephs KA, Whitwell JL, Parisi JE, Knopman DS, Boeve BF, Geda YE, Jack CR Jr, Petersen RC, Dickson DW (2008) Argyrophilic grains: a distinct disease or an additive pathology? Neurobiol Aging 29:566–573

    Article  CAS  PubMed  Google Scholar 

  39. Kang DE, Pietrzik CU, Baum L, Chevallier N, Merriam DE, Kounnas MZ, Wagner SL, Troncoso JC, Kawas CH, Katzman R, Koo EH (2000) Modulation of amyloid beta-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor-related protein pathway. J Clin Invest 106:1159–1166

    Article  CAS  PubMed  Google Scholar 

  40. Kang DE, Saitoh T, Chen X, Xia Y, Masliah E, Hansen LA, Thomas RG, Thal LJ, Katzman R (1997) Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer’s disease. Neurology 49:56–61

    CAS  PubMed  Google Scholar 

  41. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300:486–489

    Article  CAS  PubMed  Google Scholar 

  42. Kim KS, Miller DL, Sapienza VJ, Chen C-MJ, Bai C, Grundke-Iqbal I, Currie JR, Wisniewski HM (1988) Production and characterization of monoclonal antibodies reactive to synthetic cerebrovascular amyloid peptide. Neurosci Res Commun 2:121–130

    CAS  Google Scholar 

  43. Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, Paul SM (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10:719–726

    Article  CAS  PubMed  Google Scholar 

  44. Kölsch H, Lüthjohann D, Jessen F, Popp J, Hentschel F, Kelemen P, Schmitz S, Maier W, Heun R (2009) CYP46A1 variants influence Alzheimer’s disease risk and brain cholesterol metabolism. Eur Psychiatry 24:183–190

    Article  PubMed  Google Scholar 

  45. Kölsch H, Lütjohann D, Ludwig M, Schulte A, Ptok U, Jessen F, von Bergmann K, Rao ML, Maier W, Heun R (2002) Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer’s disease. Mol Psychiatry 7:899–902

    Article  PubMed  Google Scholar 

  46. Li Y, Liu L, Barger SW, Griffin WS (2003) Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 23:1605–1611

    CAS  PubMed  Google Scholar 

  47. McGeer PL, Akiyama H, Itagaki S, McGeer EG (1989) Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett 107:341–346

    Article  CAS  PubMed  Google Scholar 

  48. Milton ID, Banner SJ, Ince PG, Piggott NH, Fray AE, Thatcher N, Horne CH, Shaw PJ (1997) Expression of the glial glutamate transporter EAAT2 in the human CNS: an immunohistochemical study. Brain Res Mol Brain Res 52:17–31

    Article  CAS  PubMed  Google Scholar 

  49. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, 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 41:479–486

    CAS  PubMed  Google Scholar 

  50. Moestrup SK, Gliemann J, Pallesen G (1992) Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res 269:375–382

    Article  CAS  PubMed  Google Scholar 

  51. Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L (2001) Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 58:397–405

    Article  CAS  PubMed  Google Scholar 

  52. Narita M, Holtzman DM, Schwartz AL, Bu G (1997) Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J Neurochem 69:1904–1911

    CAS  PubMed  Google Scholar 

  53. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332

    Article  CAS  PubMed  Google Scholar 

  54. Papassotiropoulos A, Lambert JC, Wavrant-De Vrieze F, Wollmer MA, von der Kammer H, Streffer JR, Maddalena A, Huynh KD, Wolleb S, Lütjohann D, Schneider B, Thal DR, Grimaldi LM, Tsolaki M, Kapaki E, Ravid R, Konietzko U, Hegi T, Pasch T, Jung H, Braak H, Amouyel P, Rogaev EI, Hardy J, Hock C, Nitsch RM (2005) Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer’s disease. Neurodegener Dis 2:233–241

    Article  CAS  PubMed  Google Scholar 

  55. Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S, Thal D, Nicosia F, Iakovidou V, Maddalena A, Lütjohann D, Ghebremedhin E, Hegi T, Pasch T, Traxler M, Bruhl A, Benussi L, Binetti G, Braak H, Nitsch RM, Hock C (2003) Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol 60:29–35

    Article  PubMed  Google Scholar 

  56. Reid PC, Urano Y, Kodama T, Hamakubo T (2007) Alzheimer’s disease: cholesterol, membrane rafts, isoprenoids and statins. J Cell Mol Med 11:383–392

    Article  CAS  PubMed  Google Scholar 

  57. Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, Ball MJ (1993) beta-Amyloid-(1–42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci USA 90:10836–10840

    Article  CAS  PubMed  Google Scholar 

  58. 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 14:457–466

    Article  CAS  PubMed  Google Scholar 

  59. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73:2061–2070

    Article  CAS  PubMed  Google Scholar 

  60. Sasaki S, Warita H, Abe K, Komori T, Iwata M (2001) EAAT1 and EAAT2 immunoreactivity in transgenic mice with a G93A mutant SOD1 gene. Neuroreport 12:1359–1362

    Article  CAS  PubMed  Google Scholar 

  61. Sautiere PE, Sindou P, Couratier P, Hugon J, Wattez A, Delacourte A (1992) Tau antigenic changes induced by glutamate in rat primary culture model: a biochemical approach. Neurosci Lett 140:206–210

    Article  CAS  PubMed  Google Scholar 

  62. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981

    Article  CAS  PubMed  Google Scholar 

  63. Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2008) Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses. Neurobiol Aging 31(7):1145–1152

    Article  PubMed  Google Scholar 

  64. Tekirian TL, Saido TC, Markesbery WR, Russell MJ, Wekstein DR, Patel E, Geddes JW (1998) N-terminal heterogeneity of parenchymal and cerebrovascular Abeta deposits. J Neuropathol Exp Neurol 57:76–94

    Article  CAS  PubMed  Google Scholar 

  65. Thal DR (2002) Excitatory amino acid transporter EAAT-2 in tangle-bearing neurons in Alzheimer’s disease. Brain Pathol 12:405–411

    CAS  Google Scholar 

  66. Thal DR, Capetillo-Zarate E, Larionov S, Staufenbiel M, Zurbruegg S, Beckmann N (2009) Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol Aging 30:1936–1948

    Article  CAS  PubMed  Google Scholar 

  67. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD (2003) Vascular pathology in Alzheimer’s disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287–1301

    PubMed  Google Scholar 

  68. Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293

    PubMed  Google Scholar 

  69. Thal DR, Griffin WST, De Vos RAI, Ghebremedhin E (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 115:599–609

    Article  CAS  PubMed  Google Scholar 

  70. Thal DR, Larionov S, Abramowski D, Wiederhold KH, Van Dooren T, Yamaguchi H, Haass C, Van Leuven F, Staufenbiel M, Capetillo-Zarate E (2007) Occurrence and co-localization of amyloid beta-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice. Neurobiol Aging 28:1221–1230

    Article  CAS  PubMed  Google Scholar 

  71. Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Abeta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    PubMed  Google Scholar 

  72. Thal DR, Rüb U, Schultz C, Sassin I, Ghebremedhin E, Del Tredici K, Braak E, Braak H (2000) Sequence of Abeta-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol 59:733–748

    CAS  PubMed  Google Scholar 

  73. Thal DR, Sassin I, Schultz C, Haass C, Braak E, Braak H (1999) Fleecy amyloid deposits in the internal layers of the human entorhinal cortex are comprised of N-terminal truncated fragments of Abeta. J Neuropathol Exp Neurol 58:210–216

    Article  CAS  PubMed  Google Scholar 

  74. Thal DR, Schultz C, Botez G, Del Tredici K, Mrak RE, Griffin WS, Wiestler OD, Braak H, Ghebremedhin E (2005) The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer’s disease-related pathology. Neuropathol Appl Neurobiol 31:270–279

    Article  CAS  PubMed  Google Scholar 

  75. Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM (2010) APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol 67:93–98

    Article  PubMed  Google Scholar 

  76. The National Institute on Aging (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2

    Article  Google Scholar 

  77. Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CL (2010) Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer’s disease. J Neurochem 113:978–989

    Article  CAS  PubMed  Google Scholar 

  78. Utter S, Tamboli IY, Walter J, Rijal Upadhaya A, Birkenmeier G, Pietrzik CU, Ghebremedhin E, Thal DR (2008) Cerebral small vessel disease-induced apolipoprotein E leakage is associated with Alzheimer disease and the accumulation of amyloid beta-protein in perivascular astrocytes. J Neuropathol Exp Neurol 67:842–856

    Article  CAS  PubMed  Google Scholar 

  79. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323

    Article  CAS  PubMed  Google Scholar 

  80. Wang Y, Muneton S, Sjovall J, Jovanovic JN, Griffiths WJ (2008) The effect of 24S-hydroxycholesterol on cholesterol homeostasis in neurons: quantitative changes to the cortical neuron proteome. J Proteome Res 7:1606–1614

    Article  CAS  PubMed  Google Scholar 

  81. Weller RO (1998) Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. J Neuropathol Exp Neurol 57:885–894

    Article  CAS  PubMed  Google Scholar 

  82. Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117:1–14

    Article  CAS  PubMed  Google Scholar 

  83. Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE (1998) Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol 153:725–733

    CAS  PubMed  Google Scholar 

  84. Wilcock DM, Vitek MP, Colton CA (2009) Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer’s disease. Neuroscience 159:1055–1069

    Article  CAS  PubMed  Google Scholar 

  85. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279–282

    Article  CAS  PubMed  Google Scholar 

  86. Zhong N, Ramaswamy G, Weisgraber KH (2009) Apolipoprotein E4 domain interaction induces endoplasmic reticulum stress and impairs astrocyte function. J Biol Chem 284:27273–27280

    Article  CAS  PubMed  Google Scholar 

  87. Zhong N, Scearce-Levie K, Ramaswamy G, Weisgraber KH (2008) Apolipoprotein E4 domain interaction: synaptic and cognitive deficits in mice. Alzheimers Dement 4:179–192

    Article  CAS  PubMed  Google Scholar 

  88. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Irina Lungrin, Heike Korff, Sue Woodward, Uta Enderlein, Nicole Kolosnjaji, Katrin Pruy, Alice Yeates, and Claudia Berchtold for technical help. The authors thank Drs. Peter Müller, Mario Orantes (Offenbach am Main), and Rob A.I. de Vos (Enschede) for providing autopsy tissue.

Conflict of interest statement

This study was supported by DFG-grants TH624/4-1 and TH624/4-2 (DRT), GH12/2-2 (EG), and NIH-NIA-grant AG12411 (WSTG). Heike Kölsch is an employee of IQWIG (Institut für Qualität und Wirtschaftlichkeit im Gesundsheitswesen) Cologne, Germany.

Author information

Author notes

  1. Heike Kölsch

    Present address: IQWIG, Dillenburger Strasse 27, 51105, Cologne, Germany

Authors and Affiliations

  1. Laboratory of Neuropathology, Institute of Pathology, University of Ulm, Albert Einstein Allee 11, 89081, Ulm, Germany

    Dietmar Rudolf Thal & Estifanos Ghebremedhin

  2. Department of Molecular Psychology, University of Basel, 4055, Basel, Switzerland

    Andreas Papassotiropoulos

  3. Laboratory of Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, 351-0198, Japan

    Takaomi C. Saido

  4. Donald W. Reynolds Center on Aging, UAMS, Little Rock, AR, USA

    W. Sue T. Griffin

  5. Geriatric Research Education and Clinical Center, Veteran’s Affairs Medical Center, Little Rock, AR, USA

    W. Sue T. Griffin

  6. Department of Pathology, University of Toledo, Toledo, OH, USA

    Robert E. Mrak

  7. Department of Psychiatry, University of Bonn, 53105, Bonn, Germany

    Heike Kölsch

  8. Clinical Neuroanatomy (Department of Neurology), Center for Clinical Research, University of Ulm, 89081, Ulm, Germany

    Kelly Del Tredici

  9. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

    Johannes Attems

  10. Institute for Clinical Neuroanatomy, J. W. Goethe University, 60590, Frankfurt am Main, Germany

    Estifanos Ghebremedhin

  11. Department of Anatomy and Developmental Biology, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia

    Estifanos Ghebremedhin

Authors
  1. Dietmar Rudolf Thal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Papassotiropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takaomi C. Saido
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Sue T. Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert E. Mrak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heike Kölsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kelly Del Tredici
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Johannes Attems
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Estifanos Ghebremedhin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dietmar Rudolf Thal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thal, D.R., Papassotiropoulos, A., Saido, T.C. et al. Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease. Acta Neuropathol 120, 169–183 (2010). https://doi.org/10.1007/s00401-010-0707-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0707-9

Keywords

Search

Navigation