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Differential deposition of amyloid β peptides in cerebral amyloid angiopathy associated with Alzheimer’s disease and vascular dementia

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Abstract

Cerebral amyloid angiopathy (CAA) caused by deposition of amyloid β (Aβ) peptides in the cerebrovasculature, involves degeneration of normal vascular components and increases the risk of infarction and cerebral hemorrhage. Accumulating evidence suggests that sporadic CAA is also a significant contributor to cognitive decline and dementia in the elderly. However, the mechanisms by which CAA arises are poorly understood. While neuronal sources of Aβ peptides are sufficient to cause CAA in transgenic mice overexpressing the amyloid precursor protein, there is reason to believe that in aging man, vascular disease modulates the disease process. To better understand CAA mechanisms in dementia, we assessed the frontal cortex of 62 consecutive cases of Alzheimer’s disease (AD), vascular dementia (VaD), and mixed dementia (MD) using immunohistochemistry with antibodies to Aβ, smooth muscle actin and the carboxyl-terminal peptides to detect Aβ(40) and Aβ(42). While vascular Aβ deposition was invariably associated with smooth muscle degeneration as indicated by absence of smooth muscle cell actin reactivity, VaD/MD cases exhibited markedly more vascular Aβ(42) deposits and smooth muscle actin loss compared to AD cases with similar degrees of CAA and Aβ(40) deposition. This suggests that distinct mechanisms are responsible for the differential deposition of Aβ in CAA associated with AD and that associated with ischemic/cerebrovascular disease. It is plausible that experimental studies on the effects of cerebrovascular disease on Aβ production and elimination will yield important clues on the pathogenesis of CAA.

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References

  1. Alonzo NC, Hyman BT, Rebeck GW, Greenberg SM (1998) Progression of cerebral amyloid angiopathy: accumulation of amyloid-beta40 in affected vessels. J Neuropathol Exp Neurol 57:353–359

    Article  PubMed  CAS  Google Scholar 

  2. Attems J (2005) Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms. Acta Neuropathol 110:345–359

    Article  PubMed  CAS  Google Scholar 

  3. Attems J, Lintner F, Jellinger KA (2004) Amyloid beta peptide 1–42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology. Acta Neuropathol 107:283–291

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Brun A, Englund E (1981) Regional pattern of degeneration in Alzheimer’s disease: neuronal loss and histopathological grading. Histopathology 5:549–564

    Article  PubMed  CAS  Google Scholar 

  6. Brun A, Gustafson L (1993) The longitudinal dementia study: a 25-year perspective on neuropathology, differential diagnosis and treatment. In: Corain B, Iqbal K, Nicolini M, Winblad B, Wisniewski H, Zatta P (eds) Alzheimer’s disease—advances in clinical and basic research. Wiley, New York, pp 3–18

    Google Scholar 

  7. Cadavid D, Mena H, Koeller K, Frommelt RA (2000) Cerebral beta amyloid angiopathy is a risk factor for cerebral ischemic infarction. A case control study in human brain biopsies. J Neuropathol Exp Neurol 59:768–773

    PubMed  CAS  Google Scholar 

  8. Eisenhauer PB, Johnson RJ, Wells JM, Davies TA, Fine RE (2000) Toxicity of various amyloid beta peptide species in cultured human blood–brain barrier endothelial cells: increased toxicity of Dutch-type mutant. J Neurosci Res 60:804–810

    Article  PubMed  CAS  Google Scholar 

  9. Fernando MS, Ince PG (2004) MRC Cognitive Function and Ageing Neuropathology Study Group. Vascular pathologies and cognition in a population-based cohort of elderly people. J Neurol Sci 226:13–17

    Article  PubMed  Google Scholar 

  10. Gravina SA, Ho L, Eckman CB, Long KE, Otvos L Jr, Younkin LH, Suzuki N, Younkin SG (1995) Amyloid beta protein (A beta) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). J Biol Chem 270:7013–7016

    Article  PubMed  CAS  Google Scholar 

  11. Gray F, Dubas F, Roullet E, Escourolle R (1985) Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy. Ann Neurol 18:54–59

    Article  PubMed  CAS  Google Scholar 

  12. Greenberg SM, Gurol ME, Rosand J, Smith EE (2004) Amyloid angiopathy-related vascular cognitive impairment. Stroke 35:2616–2619

    Article  PubMed  Google Scholar 

  13. Haglund M, Englund E (2002) Cerebral amyloid angiopathy, white matter lesions and Alzheimer encephalopathy—a histopathological assessment. Dement Geriatr Cogn Disord 14:161–166

    Article  PubMed  CAS  Google Scholar 

  14. Haglund M, Sjobeck M, Englund E (2004) Severe cerebral amyloid angiopathy characterizes an underestimated variant of vascular dementia. Dement Geriatr Cogn Disord 18:132–137

    Article  PubMed  Google Scholar 

  15. 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 13:45–53

    Article  PubMed  CAS  Google Scholar 

  16. Jarrett JT, Berger EP, Lansbury PT (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32:4693–4697

    Article  PubMed  CAS  Google Scholar 

  17. Jellinger K (1977) Cerebrovascular amyloidosis with cerebral hemorrhage. J Neurol 214:195–206

    Article  PubMed  CAS  Google Scholar 

  18. Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T (2004) Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci 226:75–80

    Article  PubMed  Google Scholar 

  19. Kalaria RN, Thomas A, Oakley A, Ince P, Tamaoka A, Mori H, Kenny RA, Ballard C (2003) Cerebrovascular amyloidosis and dementia. Curr Med Chem Immun Endoc Metab Agents 4:317–327

    Article  Google Scholar 

  20. Kawai M, Kalaria RN, Cras P, Siedlak SL, Velasco ME, Shelton ER, Chan HW, Greenberg BD, Perry G (1993) Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease. Brain Res 623:142–146

    Article  PubMed  CAS  Google Scholar 

  21. Mori H, Takio K, Ogawara M, Selkoe DJ (1992) Mass spectrometry of purified amyloid beta protein in Alzheimer’s disease. J Biol Chem 267:17082–17086

    PubMed  CAS  Google Scholar 

  22. Nicoll JA, Yamada M, Frackowiak J, Mazur-Kolecka B, Weller RO (2004) Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease. Pro-CAA position statement. Neurobiol Aging 25:589–597

    Article  PubMed  CAS  Google Scholar 

  23. Olichney JM, Hansen LA, Hofstetter R, Grundman R, Katzman R, Thal LJ (1995) Cerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol 52:702–708

    PubMed  CAS  Google Scholar 

  24. Rensink AA, de Waal RM, Kremer B, Verbeek MM (2003) Pathogenesis of cerebral amyloid angiopathy. Brain Res Brain Res Rev 43:207–223

    Article  PubMed  CAS  Google Scholar 

  25. Revesz T, Holton JL, Lashley T, Plant G, Rostagno A, Ghiso J, Frangione B (2002) Sporadic and familial cerebral amyloid angiopathies. Brain Pathol 12:343–357

    PubMed  Google Scholar 

  26. Rhodin JA, Thomas TN, Clark L, Garces A, Bryant M (2003) In vivo cerebrovascular actions of amyloid beta-peptides and the protective effect of conjugated estrogens. J Alzheimers Dis 5:275–286

    PubMed  CAS  Google Scholar 

  27. Roher AE, Lowenson JD, Clarke S, Wolkow C, Wang R, Cotter RJ, Reardon IM, Zurcher-Neely HA, Heinrikson RL, Ball MJ, Greenberg B (1993) Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer’s disease. J Biol Chem 268:3072–3083

    PubMed  CAS  Google Scholar 

  28. Sadowski M, Pankiewicz J, Scholtzova H, Li YS, Quartermain D, Duff K, Wisniewski T (2004) Links between the pathology of Alzheimer’s disease and vascular dementia. Neurochem Res 29:1257–1266

    Article  PubMed  CAS  Google Scholar 

  29. Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) Beta-amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168–171

    Article  PubMed  CAS  Google Scholar 

  30. Thomas A, Ballard C, Kenny RA, O’Brien J, Oakley A, Kalaria R (2005) Correlation of entorhinal amyloid with memory in Alzheimer’s and vascular but not lewy body dementia. Dement Geriatr Cogn Disord 19:57–60

    Article  PubMed  CAS  Google Scholar 

  31. Tian J, Shi J, Bailey K, Mann DM (2003) Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer’s disease. Neurosci Lett 352:137–140

    Article  PubMed  CAS  Google Scholar 

  32. Verbeek MM, de Waal RM, Schipper JJ, Van Nostrand WE (1997) Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem 68:1135–1141

    Article  PubMed  CAS  Google Scholar 

  33. 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

    PubMed  CAS  Google Scholar 

  34. Weller RO, Yow HY, Preston SD, Mazanti I, Nicoll JA (2002) Cerebrovascular disease is a major factor in the failure of elimination of A beta from the aging human brain: implications for therapy of Alzheimer’s disease. Ann N Y Acad Sci 977:162–168

    Article  PubMed  CAS  Google Scholar 

  35. Zhang WW, Lempessi H, Olsson Y (1998) Amyloid angiopathy of the human brain: immunohistochemical studies using markers for components of extracellular matrix, smooth muscle actin and endothelial cells. Acta Neuropathol 96:558–563

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank Kerstin Sturesson and Arthur Oakley for technical assistance. MH and EE are supported by the Swedish Alzheimer Foundation. RK and JS are supported by grants from Medical Research Council, UK, The Alzheimer’s Research Trust, UK and the European Commission QLK6-CT-1999-02112.

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Authors and Affiliations

  1. Division of Neuropathology, Department of Pathology and Cytology, Lund University Hospital, 221 85, Lund, Sweden

    Mattias Haglund & Elisabet Englund

  2. Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, United Kingdom

    Raj Kalaria & Janet Y. Slade

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  1. Mattias Haglund
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  2. Raj Kalaria
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  4. Elisabet Englund
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Correspondence to Mattias Haglund.

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Haglund, M., Kalaria, R., Slade, J.Y. et al. Differential deposition of amyloid β peptides in cerebral amyloid angiopathy associated with Alzheimer’s disease and vascular dementia. Acta Neuropathol 111, 430–435 (2006). https://doi.org/10.1007/s00401-006-0054-z

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  • DOI: https://doi.org/10.1007/s00401-006-0054-z

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