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01-08-2010 | Original Paper

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

Authors: Dietmar Rudolf Thal, Andreas Papassotiropoulos, Takaomi C. Saido, W. Sue T. Griffin, Robert E. Mrak, Heike Kölsch, Kelly Del Tredici, Johannes Attems, Estifanos Ghebremedhin

Published in: Acta Neuropathologica | Issue 2/2010

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.

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

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

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

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

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 317:837–848PubMed

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

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 83:623–632CrossRefPubMed

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

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

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 112:389–404CrossRefPubMed

11.

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

12.

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

13.

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

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 24:197–211CrossRefPubMed

15.

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

16.

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

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 31:11–19CrossRefPubMed

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 1019:24–28CrossRefPubMed

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 261:921–923CrossRefPubMed

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 118:4002–4013CrossRefPubMed

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 14:1097–1105CrossRefPubMed

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 354:919–920CrossRefPubMed

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 278:1349–1356CrossRefPubMed

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 79:229–231CrossRefPubMed

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 28:308–313CrossRefPubMed

26.

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

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 86:7611–7615CrossRefPubMed

28.

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

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 83:4913–4917CrossRefPubMed

30.

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

31.

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

32.

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

33.

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

34.

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

35.

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

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

37.

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

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 29:566–573CrossRefPubMed

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 106:1159–1166CrossRefPubMed

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 49:56–61PubMed

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 300:486–489CrossRefPubMed

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

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 10:719–726CrossRefPubMed

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 24:183–190CrossRefPubMed

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 7:899–902CrossRefPubMed

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 23:1605–1611PubMed

47.

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

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 52:17–31CrossRefPubMed

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 41:479–486PubMed

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 269:375–382CrossRefPubMed

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 58:397–405CrossRefPubMed

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 69:1904–1911PubMed

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 43:321–332CrossRefPubMed

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 2:233–241CrossRefPubMed

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 60:29–35CrossRefPubMed

56.

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

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 90:10836–10840CrossRefPubMed

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 14:457–466CrossRefPubMed

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 73:2061–2070CrossRefPubMed

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 12:1359–1362CrossRefPubMed

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 140:206–210CrossRefPubMed

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 90:1977–1981CrossRefPubMed

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):1145–1152CrossRefPubMed

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 57:76–94CrossRefPubMed

65.

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

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 30:1936–1948CrossRefPubMed

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 62:1287–1301PubMed

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 61:282–293PubMed

69.

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

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 28:1221–1230CrossRefPubMed

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 58:1791–1800PubMed

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 59:733–748PubMed

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 58:210–216CrossRefPubMed

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 31:270–279CrossRefPubMed

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 67:93–98CrossRefPubMed

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–S2CrossRef

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 113:978–989CrossRefPubMed

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 67:842–856CrossRefPubMed

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 105:19318–19323CrossRefPubMed

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 7:1606–1614CrossRefPubMed

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 57:885–894CrossRefPubMed

82.

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

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 153:725–733PubMed

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 159:1055–1069CrossRefPubMed

85.

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

86.

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

87.

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

88.

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

Title: Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease
Authors: Dietmar Rudolf Thal
Andreas Papassotiropoulos
Takaomi C. Saido
W. Sue T. Griffin
Robert E. Mrak
Heike Kölsch
Kelly Del Tredici
Johannes Attems
Estifanos Ghebremedhin
Publication date: 01-08-2010
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 2/2010
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-010-0707-9

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

Abstract

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