Translational Stroke Research

, Volume 5, Issue 3, pp 330–337 | Cite as

Alzheimer’s Silent Partner: Cerebral Amyloid Angiopathy

Original Article

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, which completely lacks a viable, long-term therapeutic intervention. This is partly due to an incomplete understanding of AD etiology and the possible confounding factors associated with its genotypic and phenotypic heterogeneity. Cerebral amyloid angiopathy (CAA) is a common, yet frequently overlooked, pathology associated with AD. CAA manifests with deposition amyloid-beta (Aβ) within the smooth muscle layer of cerebral arteries and arterioles. The role of Aβ in AD and CAA pathophysiology has long been controversial. Although it has demonstrated toxicity at super-physiological levels in vitro, Aβ load does not necessarily correlate with cognitive demise in humans. In this review, we describe the contributions of CAA to AD pathophysiology and important pathomechanisms that may lead to vascular fragility and hemorrhages. Additionally, we discuss the effect of Aβ on smooth muscle cell phenotype and viability, especially in terms of the complement cascade.

Keywords

Complement Microbleed Membrane attack complex C3 LRP1 RAGE 

Abbreviations

Amyloid beta

AD

Alzheimer’s disease

APP

Amyloid precursor protein

BMB

Brain microbleed

C3

Complement component 3

CAA

Cerebral amyloid angiopathy

ICH

Intracerebral hemorrhage

MAC

Membrane attack complex

SMC

Smooth muscle cell

Notes

Conflict of Interest

This article does not contain any studies with human or animal subjects. Tanya Cupino and Matthew Zabel declare that they have no conflict of interest.

References

  1. 1.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging—Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–9. doi: 10.1016/j.jalz.2011.03.005.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Alzheimer’s A. Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2012;8(2):131–68. doi: 10.1016/j.jalz.2012.02.001.CrossRefGoogle Scholar
  3. 3.
    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6. doi: 10.1126/science.1072994.PubMedCrossRefGoogle Scholar
  4. 4.
    Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30(4):572–80. doi: 10.1002/ana.410300410.PubMedCrossRefGoogle Scholar
  5. 5.
    Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci. 2010;13(7):812–8. doi: 10.1038/nn.2583.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Waring SC, Rosenberg RN. Genome-wide association studies in Alzheimer disease. Arch Neurol. 2008;65(3):329–34. doi: 10.1001/archneur.65.3.329.PubMedCrossRefGoogle Scholar
  7. 7.
    Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Human Genet. 1999;65(3):664–70. doi: 10.1086/302553.CrossRefGoogle Scholar
  8. 8.
    Nochlin D, van Belle G, Bird TD, Sumi SM. Comparison of the severity of neuropathologic changes in familial and sporadic Alzheimer’s disease. Alzheimer Dis Assoc Disord. 1993;7(4):212–22.PubMedGoogle Scholar
  9. 9.
    Glenner GG, Wong CW. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984;122(3):1131–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Castello MA, Soriano S. Rational heterodoxy: cholesterol reformation of the amyloid doctrine. Ageing Res Rev. 2012;12(1):282–8. doi: 10.1016/j.arr.2012.06.007.PubMedCrossRefGoogle Scholar
  11. 11.
    Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. New Engl J Med. 2013;369(4):341–50. doi: 10.1056/NEJMoa1210951.PubMedCrossRefGoogle Scholar
  12. 12.
    Tayeb HO, Murray ED, Price BH, Tarazi FI. Bapineuzumab and solanezumab for Alzheimer’s disease: is the ‘amyloid cascade hypothesis’ still alive? Exp Opin Biol Ther. 2013;13(7):1075–84. doi: 10.1517/14712598.2013.789856.CrossRefGoogle Scholar
  13. 13.
    Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke. 1987;18(2):311–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO. 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. 2003;29(2):106–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Tomonaga M. Cerebral amyloid angiopathy in the elderly. J Am Geriatr Soc. 1981;29(4):151–7.PubMedGoogle Scholar
  16. 16.
    Vinters HV, Gilbert JJ. Cerebral amyloid angiopathy: incidence and complications in the aging brain: II. The distribution of amyloid vascular changes. Stroke. 1983;14(6):924–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology. 2002;58(11):1629–34.PubMedCrossRefGoogle Scholar
  18. 18.
    Attems J, Quass M, Jellinger KA, Lintner F. Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology. J Neurol Sci. 2007;257(1–2):49–55. doi: 10.1016/j.jns.2007.01.013.PubMedCrossRefGoogle Scholar
  19. 19.
    Attems J. Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms. Acta Neuropathol. 2005;110(4):345–59. doi: 10.1007/s00401-005-1074-9.PubMedCrossRefGoogle Scholar
  20. 20.
    Masuda J. Incidence of cerebral amyloid angiopathy in autopsy cases in Hisayama, Japan. Nihon Ronen Igakkai Zasshi Jpn J Geriatr. 1985;22(2):138–43.Google Scholar
  21. 21.
    Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol. 2003;62(12):1287–301.PubMedGoogle Scholar
  22. 22.
    Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T. Members of the familial Alzheimer’s disease pathology study G. Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer’s disease. Am J Pathol. 2001;158(6):2165–75.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson Jr EP. Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol. 1991;30(5):637–49. doi: 10.1002/ana.410300503.PubMedCrossRefGoogle Scholar
  24. 24.
    Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris JC, Beekly D, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience. Part XV. Neurology. 1996;46(6):1592–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Jellinger KA, Attems J. Incidence of cerebrovascular lesions in Alzheimer’s disease: a postmortem study. Acta Neuropathol. 2003;105(1):14–7. doi: 10.1007/s00401-002-0634-5.PubMedGoogle Scholar
  26. 26.
    Lue LF, Brachova L, Civin WH, Rogers J. Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. J Neuropathol Exp Neurol. 1996;55(10):1083–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Greenberg SM, O’Donnell HC, Schaefer PW, Kraft E. MRI detection of new hemorrhages: potential marker of progression in cerebral amyloid angiopathy. Neurology. 1999;53(5):1135–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Kirsch W, McAuley G, Holshouser B, Petersen F, Ayaz M, Vinters HV, et al. Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia. J Alzheimers Dse. 2009;17(3):599–609. doi: 10.3233/JAD-2009-1073.Google Scholar
  29. 29.
    Roob G, Lechner A, Schmidt R, Flooh E, Hartung HP, Fazekas F. Frequency and location of microbleeds in patients with primary intracerebral hemorrhage. Stroke. 2000;31(11):2665–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Hanyu H, Tanaka Y, Shimizu S, Takasaki M, Fujita H, Kaneko N, et al. Cerebral microbleeds in Binswanger’s disease: a gradient-echo T2*-weighted magnetic resonance imaging study. Neurosci Lett. 2003;340(3):213–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Nakata Y, Shiga K, Yoshikawa K, Mizuno T, Mori S, Yamada K, et al. Subclinical brain hemorrhages in Alzheimer’s disease: evaluation by magnetic resonance T2*-weighted images. Ann N Y Acad Sci. 2002;977:169–72.PubMedCrossRefGoogle Scholar
  32. 32.
    Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain. 2007;130(Pt 8):1988–2003. doi: 10.1093/brain/awl387.PubMedCrossRefGoogle Scholar
  33. 33.
    Jeerakathil T, Wolf PA, Beiser A, Massaro J, Seshadri S, D’Agostino RB, et al. Stroke risk profile predicts white matter hyperintensity volume: the Framingham study. Stroke. 2004;35(8):1857–61. doi: 10.1161/01.STR.0000135226.53499.85.PubMedCrossRefGoogle Scholar
  34. 34.
    Tsushima Y, Tanizaki Y, Aoki J, Endo K. MR detection of microhemorrhages in neurologically healthy adults. Neuroradiology. 2002;44(1):31–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Roob G, Schmidt R, Kapeller P, Lechner A, Hartung HP, Fazekas F. MRI evidence of past cerebral microbleeds in a healthy elderly population. Neurology. 1999;52(5):991–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Lara FA, Kahn SA, da Fonseca AC, Bahia CP, Pinho JP, Graca-Souza AV, et al. On the fate of extracellular hemoglobin and heme in brain. J Cereb Blood Flow Metab. 2009;29(6):1109–20. doi: 10.1038/jcbfm.2009.34.PubMedCrossRefGoogle Scholar
  37. 37.
    Schrag M, Mueller C, Oyoyo U, Smith MA, Kirsch WM. Iron, zinc and copper in the Alzheimer’s disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog Neurobiol. 2011;94(3):296–306. doi: 10.1016/j.pneurobio.2011.05.001.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Brambilla R, Couch Y, Lambertsen KL. The effect of stroke on immune function. Mol Cell Neurosci. 2013;53:26–33. doi: 10.1016/j.mcn.2012.08.011.PubMedCrossRefGoogle Scholar
  39. 39.
    Rosand J, Muzikansky A, Kumar A, Wisco JJ, Smith EE, Betensky RA, et al. Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy. Ann Neurol. 2005;58(3):459–62. doi: 10.1002/ana.20596.PubMedCrossRefGoogle Scholar
  40. 40.
    Greenberg SM, Vonsattel JP. Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke. 1997;28(7):1418–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001;56(4):537–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Biffi A, Halpin A, Towfighi A, Gilson A, Busl K, Rost N, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology. 2010;75(8):693–8. doi: 10.1212/WNL.0b013e3181eee40f.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Vernooij MW, Haag MD, van der Lugt A, Hofman A, Krestin GP, Stricker BH, et al. Use of antithrombotic drugs and the presence of cerebral microbleeds: the Rotterdam scan study. Arch Neurol. 2009;66(6):714–20. doi: 10.1001/archneurol.2009.42.PubMedCrossRefGoogle Scholar
  44. 44.
    Thoonsen H, Richard E, Bentham P, Gray R, van Geloven N, De Haan RJ, et al. Aspirin in Alzheimer’s disease: increased risk of intracerebral hemorrhage: cause for concern? Stroke. 2010;41(11):2690–2. doi: 10.1161/STROKEAHA.109.576975.PubMedCrossRefGoogle Scholar
  45. 45.
    Tolppanen AM, Lavikainen P, Solomon A, Kivipelto M, Soininen H, Hartikainen S. Incidence of stroke in people with Alzheimer disease: a national register-based approach. Neurology. 2013;80(4):353–8. doi: 10.1212/WNL.0b013e31827f08c5.PubMedCrossRefGoogle Scholar
  46. 46.
    Dennis MS, Burn JP, Sandercock PA, Bamford JM, Wade DT, Warlow CP. Long-term survival after first-ever stroke: the Oxfordshire Community Stroke Project. Stroke. 1993;24(6):796–800.PubMedCrossRefGoogle Scholar
  47. 47.
    Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2(1):43–53.PubMedCrossRefGoogle Scholar
  48. 48.
    Sacco S, Marini C, Toni D, Olivieri L, Carolei A. Incidence and 10-year survival of intracerebral hemorrhage in a population-based registry. Stroke. 2009;40(2):394–9. doi: 10.1161/STROKEAHA.108.523209.PubMedCrossRefGoogle Scholar
  49. 49.
    Cadilhac DA, Dewey HM, Vos T, Carter R, Thrift AG. The health loss from ischemic stroke and intracerebral hemorrhage: evidence from the North East Melbourne Stroke Incidence Study (NEMESIS). Health Qual Life Outcomes. 2010;8:49. doi: 10.1186/1477-7525-8-49.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Massaro AR, Sacco RL, Mohr JP, Foulkes MA, Tatemichi TK, Price TR, et al. Clinical discriminators of lobar and deep hemorrhages: the Stroke Data Bank. Neurology. 1991;41(12):1881–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Itoh Y, Yamada M, Hayakawa M, Otomo E, Miyatake T. Cerebral amyloid angiopathy: a significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly. J Neurol Sci. 1993;116(2):135–41.PubMedCrossRefGoogle Scholar
  52. 52.
    Mesker DJ, Poels MM, Ikram MA, Vernooij MW, Hofman A, Vrooman HA, et al. Lobar distribution of cerebral microbleeds: the Rotterdam scan study. Arch Neurol. 2011;68(5):656–9. doi: 10.1001/archneurol.2011.93.PubMedCrossRefGoogle Scholar
  53. 53.
    Sepulcre J, Sabuncu MR, Becker A, Sperling R, Johnson KA. In vivo characterization of the early states of the amyloid-beta network. Brain. 2013;136(Pt 7):2239–52. doi: 10.1093/brain/awt146.PubMedCrossRefGoogle Scholar
  54. 54.
    Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron. 2004;43(3):333–44. doi: 10.1016/j.neuron.2004.07.017.PubMedCrossRefGoogle Scholar
  55. 55.
    Kanekiyo T, Liu CC, Shinohara M, Li J, Bu G. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer’s amyloid-beta. J Neurosci. 2012;32(46):16458–65. doi: 10.1523/JNEUROSCI.3987-12.2012.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. RAGE mediates amyloid-beta peptide transport across the blood–brain barrier and accumulation in brain. Nat Med. 2003;9(7):907–13. doi: 10.1038/nm890.PubMedCrossRefGoogle Scholar
  57. 57.
    Chow N, Bell RD, Deane R, Streb JW, Chen J, Brooks A, et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer’s phenotype. Proc Natl Acad Sci U S A. 2007;104(3):823–8. doi: 10.1073/pnas.0608251104.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Bell RD, Deane R, Chow N, Long X, Sagare A, Singh I, et al. SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol. 2009;11(2):143–53. doi: 10.1038/ncb1819.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Huang C, Wahlund LO, Svensson L, Winblad B, Julin P. Cingulate cortex hypoperfusion predicts Alzheimer’s disease in mild cognitive impairment. BMC Neurol. 2002;2:9.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ, et al. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology. 2005;234(3):851–9. doi: 10.1148/radiol.2343040197.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Armstrong RA, Cairns NJ, Patel R, Lantos PL, Rossor MN. Relationships between beta-amyloid (A beta) deposits and blood vessels in patients with sporadic and familial Alzheimer’s disease. Neurosci Lett. 1996;207(3):171–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Krahn V. The pia mater at the site of the entry of blood vessels into the central nervous system. Anat Embryol (Berl). 1982;164(2):257–63.CrossRefGoogle Scholar
  63. 63.
    Hutchings M, Weller RO. Anatomical relationships of the pia mater to cerebral blood vessels in man. J Neurosurg. 1986;65(3):316–25. doi: 10.3171/jns.1986.65.3.0316.PubMedCrossRefGoogle Scholar
  64. 64.
    Zhang ET, Inman CB, Weller RO. Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat. 1990;170:111–23.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol. 2006;238(4):962–74. doi: 10.1016/j.jtbi.2005.07.005.PubMedCrossRefGoogle Scholar
  66. 66.
    Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008;34(2):131–44. doi: 10.1111/j.1365-2990.2007.00926.x.PubMedCrossRefGoogle Scholar
  67. 67.
    Szentistvanyi I, Patlak CS, Ellis RA, Cserr HF. Drainage of interstitial fluid from different regions of rat brain. Am J Physiol. 1984;246(6 Pt 2):F835–44.PubMedGoogle Scholar
  68. 68.
    Soontornniyomkij V, Choi C, Pomakian J, Vinters HV. High-definition characterization of cerebral beta-amyloid angiopathy in Alzheimer’s disease. Hum Pathol. 2010;41(11):1601–8. doi: 10.1016/j.humpath.2010.04.011.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Cserr HF, Knopf PM. Cervical lymphatics, the blood–brain barrier and the immunoreactivity of the brain: a new view. Immunol Today. 1992;13(12):507–12. doi: 10.1016/0167-5699(92)90027-5.PubMedCrossRefGoogle Scholar
  70. 70.
    Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, et al. Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2007;27(5):909–18. doi: 10.1038/sj.jcbfm.9600419.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, et al. Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. J Clin Invest. 2000;106(12):1489–99. doi: 10.1172/JCI10498.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Dorr A, Sahota B, Chinta LV, Brown ME, Lai AY, Ma K, et al. Amyloid-beta-dependent compromise of microvascular structure and function in a model of Alzheimer’s disease. Brain. 2012;135(Pt 10):3039–50. doi: 10.1093/brain/aws243.PubMedCrossRefGoogle Scholar
  73. 73.
    Wang Z, Natte R, Berliner JA, van Duinen SG, Vinters HV. Toxicity of Dutch (E22Q) and Flemish (A21G) mutant amyloid beta proteins to human cerebral microvessel and aortic smooth muscle cells. Stroke. 2000;31(2):534–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Davis J, Van Nostrand WE. Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein. Proc Natl Acad Sci U S A. 1996;93(7):2996–3000.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    McGeer PL, Akiyama H, Itagaki S, McGeer EG. Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett. 1989;107(1–3):341–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Eikelenboom P, Hack CE, Rozemuller JM, Stam FC. Complement activation in amyloid plaques in Alzheimer’s dementia. Virchows Archiv B Cell Pathol Mol Pathol. 1989;56(4):259–62.Google Scholar
  77. 77.
    Rogers J, Schultz J, Brachova L, Lue LF, Webster S, Bradt B, et al. Complement activation and beta-amyloid-mediated neurotoxicity in Alzheimer’s disease. Res Immunol. 1992;143(6):624–30.PubMedCrossRefGoogle Scholar
  78. 78.
    Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, et al. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005;25(3):629–36. doi: 10.1523/JNEUROSCI.4337-04.2005.PubMedCrossRefGoogle Scholar
  79. 79.
    Verbeek MM, Otte-Holler I, Veerhuis R, Ruiter DJ, De Waal RM. Distribution of A beta-associated proteins in cerebrovascular amyloid of Alzheimer’s disease. Acta Neuropathol. 1998;96(6):628–36.PubMedCrossRefGoogle Scholar
  80. 80.
    Webster S, Lue LF, Brachova L, Tenner AJ, McGeer PL, Terai K, et al. Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer’s disease. Neurobiol Aging. 1997;18(4):415–21.PubMedCrossRefGoogle Scholar
  81. 81.
    Yang LB, Li R, Meri S, Rogers J, Shen Y. Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer’s disease. J Neurosci. 2000;20(20):7505–9.PubMedGoogle Scholar
  82. 82.
    Brandt J, Pippin J, Schulze M, Hansch GM, Alpers CE, Johnson RJ, et al. Role of the complement membrane attack complex (C5b-9) in mediating experimental mesangioproliferative glomerulonephritis. Kidney Int. 1996;49(2):335–43.PubMedCrossRefGoogle Scholar
  83. 83.
    Cadman ED, Puttfarcken PS. Beta-amyloid peptides initiate the complement cascade without producing a comparable effect on the terminal pathway in vitro. Exp Neurol. 1997;146(2):388–94. doi: 10.1006/exnr.1997.6540.PubMedCrossRefGoogle Scholar
  84. 84.
    Shen Y, Sullivan T, Lee CM, Meri S, Shiosaki K, Lin CW. Induced expression of neuronal membrane attack complex and cell death by Alzheimer’s beta-amyloid peptide. Brain Res. 1998;796(1–2):187–97.PubMedCrossRefGoogle Scholar
  85. 85.
    Walker DG, Dalsing-Hernandez JE, Lue LF. Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: a potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer’s disease. Microvasc Res. 2008;75(3):411–9. doi: 10.1016/j.mvr.2007.10.004.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Zabel M, Schrag M, Crofton A, Tung S, Beaufond P, Van Ornam J, et al. A shift in microglial beta-amyloid binding in Alzheimer’s disease is associated with cerebral amyloid angiopathy. Brain Pathol. 2012. doi: 10.1111/bpa.12005.PubMedGoogle Scholar
  87. 87.
    Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1094–9. doi: 10.1038/ng.439.PubMedCrossRefGoogle Scholar
  88. 88.
    Biffi A, Shulman JM, Jagiella JM, Cortellini L, Ayres AM, Schwab K, et al. Genetic variation at CR1 increases risk of cerebral amyloid angiopathy. Neurology. 2012;78(5):334–41. doi: 10.1212/WNL.0b013e3182452b40.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Biffi A, Plourde A, Shen Y, Onofrio R, Smith EE, Frosch M, et al. Screening for familial APP mutations in sporadic cerebral amyloid angiopathy. PloS ONE. 2010;5(11):e13949. doi: 10.1371/journal.pone.0013949.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Neurosurgery Center for Research, Education and TrainingLoma Linda UniversityLoma LindaUSA
  2. 2.Department of Pathology and Human AnatomyLoma Linda UniversityLoma LindaUSA

Personalised recommendations