Transgenic Mouse Models of Cerebral Amyloid Angiopathy

  • Martin C. Herzig
  • David T. Winkler
  • Lary C. Walker
  • Mathias Jucker
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 487)


The likelihood of amyloid deposition in the cerebral vasculature (cerebral amyloid angiopathy; CAA) increases with age1-3. Particularly in Alzheimer’s disease (AD), CAA can be detected in up to 90% of the patients4-6. CAA of the ß-amyloid-type (Aß-CAA) affects primarily leptomeningeal and cortical vessels and is associated with degeneration of smooth muscle cells and endothelial cells, as well as blood-brain barrier damage. Severe Aß-CAA can cause fatal cerebral hemorrhage and increases the risk of cerebral microinfarcts7-9. Genetic variations that are causative or risk factors for Aß-CAA have been identified, such as mutations in the genes for ß-amyloid precursor protein (APP), presenilins 1 and 2, and possibly cystatin C, as well as polymorphisms in apolipoprotein E3. In normal aging and AD, Aß-CAA is associated with parenchymal Aß plaques. However, Aß-CAA can also occur in the absence of plaques, as evidenced in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D)10-12.


Tg2576 Mouse Amyloid Plaque Cerebral Amyloid Angiopathy APP23 Mouse Familial British Dementia 
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  1. 1.
    Tomonaga M (1981) Cerebral amyloid angiopathy in the elderly. J Am Geriatr Soc 29: 151–157.PubMedGoogle Scholar
  2. 2.
    Vinters HV, Gilbert JJ (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14: 924–928.PubMedCrossRefGoogle Scholar
  3. 3.
    Walker LC, Durham RA (1999) Cerebrovascular amyloidosis: experimental analysis in vitro and in vivo. Histol Histopathol 14: 827–837.PubMedGoogle Scholar
  4. 4.
    Esiri MM, Wilcock GK (1986) Cerebral amyloid angiopathy in dementia and old age. J Neurol Neurosurg Psychiatry 49: 1221–1226.PubMedCrossRefGoogle Scholar
  5. 5.
    Yamada M, Tsukagoshi H, Otomo E et al. (1987) Cerebral amyloid angiopathy in the aged. J Neurol 234: 371–376.PubMedCrossRefGoogle Scholar
  6. 6.
    Yamada M (2000) Cerebral amyloid angiopathy: an overview. Neuropathology 20: 822.Google Scholar
  7. 7.
    Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18: 311–324.PubMedCrossRefGoogle Scholar
  8. 8.
    Itoh Y, Yamada M, Hayakawa M et al. (1993) Cerebral amyloid angiopathy: a significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly. J Neurol Sci 116: 135–141.PubMedCrossRefGoogle Scholar
  9. 9.
    Vonsattel JP, Myers RH, Hedley-Whyte ET et al. (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 30: 637–649.PubMedCrossRefGoogle Scholar
  10. 10.
    Wattendorff AR, Bots GT, Went LN et al. (1982) Familial cerebral amyloid angiopathy presenting as recurrent cerebral haemorrhage. J Neurol Sci 55: 121–135.PubMedCrossRefGoogle Scholar
  11. 11.
    Haan J, Hardy JA, Roos RA (1991) Hereditary cerebral hemorrhage with amyloidosis-Dutch type: its importance for Alzheimer research. Trends Neurosci 14: 231–234.PubMedCrossRefGoogle Scholar
  12. 12.
    Levy E, Carman MD, Fernandez-Madrid et al. (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248: 1124–1126.Google Scholar
  13. 13.
    Walker LC (1997) Animal models of cerebral beta-amyloid angiopathy. Brain Res Rev 25: 70–84.PubMedCrossRefGoogle Scholar
  14. 14.
    Wisniewski HM, Frackowiak J, Mazur-Kolecka B (1995) In vitro production of betaamyloid in smooth muscle cells isolated from amyloid angiopathy-affected vessels. Neurosci Lett 183: 120–123.PubMedCrossRefGoogle Scholar
  15. 15.
    Wei LH, Walker LC, Levy E (1996) Cystatin C. Icelandic-like mutation in an animal model of cerebrovascular beta-amyloidosis. Stroke 27: 2080–2085.PubMedCrossRefGoogle Scholar
  16. 16.
    Games D, Adams D, Alessandrini R, et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373: 523–527.PubMedCrossRefGoogle Scholar
  17. 17.
    Hsiao K, Chapman P, et al. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274: 99–102.PubMedCrossRefGoogle Scholar
  18. 18.
    Holtzman DM, Fagan AM, Mackey B et al. (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47: 739–747.PubMedCrossRefGoogle Scholar
  19. 19.
    Sturchler-Pierrat C, Abramowski D, Duke M et al. (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94: 13287–13292.PubMedCrossRefGoogle Scholar
  20. 20.
    Calhoun ME, Burgermeister P, Phinney AL et al. (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci U S A 96: 14088–14093.PubMedCrossRefGoogle Scholar
  21. 21.
    Winkler DT, Bondolfi L, Herzig MC et al. (2000) Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. (submitted)Google Scholar
  22. Van Dorpe J, Smeijers L, Dewachter I et al. (2000) Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons. Am J Pathol (in press)Google Scholar
  23. 23.
    Mandybur TI (1975) The incidence of cerebral amyloid angiopathy in Alzheimer’s disease. Neurology 25: 120–126.PubMedCrossRefGoogle Scholar
  24. 24.
    Ellis RJ, Olichney JM, Thal LJ et al. (1996) Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology 46: 1592–1596.Google Scholar
  25. 25.
    Wyss-Coray T, Masliah E, Mallory M et al. (1997) Amyloidogenic role of cytokine TGF-betal in transgenic mice and in Alzheimer’s disease. Nature 389: 603–606.PubMedCrossRefGoogle Scholar
  26. 26.
    Hendriks L, van Duijn CM, Cras P et al. (1992) Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet 1: 218–221.PubMedCrossRefGoogle Scholar
  27. 27.
    Cras P, van Harskamp F, Hendriks L et al. (1998) Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->GIy mutation. Acta Neuropathol 96: 253–260.PubMedCrossRefGoogle Scholar
  28. 28.
    Kumar-Singh S, Ceuterick C, Lubke U et al. (2000) Pathology of Flemish APP692 Alzheimer’s disease suggests that core containing plaques are angiocentric. Neurobiol Aging 21: S66.CrossRefGoogle Scholar
  29. 29.
    Kumar-Singh S, Dewachter I, Moechars D et al. (2000) Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation. Neurobiol Dis 7: 9–22.PubMedCrossRefGoogle Scholar
  30. 30.
    Levy E, Lopez-Otin C, Ghiso J et al. (1989) Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases. J Exp Med 169: 1771–1778.PubMedCrossRefGoogle Scholar
  31. 31.
    Vidal R, Frangione B, Rostagno A et al. (1999) A stop-codon mutation in theBRIgene associated with familial British dementia. Nature 399: 776–781.PubMedCrossRefGoogle Scholar
  32. 32.
    Vidal R, Revesz T, Rostagno A et al. (2000) A decamer duplication in the 3’ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc Natl Acad Sci USA 97: 4920–4925.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Martin C. Herzig
    • 1
  • David T. Winkler
    • 1
  • Lary C. Walker
    • 2
  • Mathias Jucker
    • 1
  1. 1.Department of NeuropathologyInstitute of Pathology, University of BaselBaselSwitzerland
  2. 2.Neuroscience TherapeuticsPfizer Ann Arbor Laboratories, Ann ArborUSA

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