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Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis

Nature Neuroscience volume 7, pages 954–960 (2004)Cite this article

Abstract

The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-β40 peptide (Aβ40) to Aβ42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AβDutch40/AβDutch42 toward AβDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Aβ species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Aβ to vascular amyloid pathology and emphasizing the differing roles of Aβ40 and Aβ42 in vascular and parenchymal amyloid pathology.

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Figure 1: Vascular amyloid in HCHWA-D brain consists of both AβDutch and Aβwt, with Aβ1–40 being the predominant peptide.
Figure 2: APPDutch mice develop cerebral amyloid angiopathy.
Figure 3: Hemorrhages and neuroinflammation in APPDutch mice.
Figure 4: Parenchymal and vascular amyloid deposition in APPwt mice.
Figure 5: Predominant parenchymal amyloid deposition in APPDutch/PS45 double-transgenic mice.

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References

  1. Haass, C. & Steiner, H. Protofibrils, the unifying toxic molecule of neurodegenerative disorders? Nat. Neurosci. 4, 859–860 (2001).

    Article  CAS  Google Scholar 

  2. Hardy, J. Amyloid, the presenilins and Alzheimer's disease. Trends. Neurosci. 20, 154–159 (1997).

    Article  CAS  Google Scholar 

  3. Selkoe, D.J. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399, A23–31 (1999).

    Article  CAS  Google Scholar 

  4. Levy, E. et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).

    Article  CAS  Google Scholar 

  5. Wattendorff, A.R., Bots, G.T., Went, L.N. & Endtz, L.J. Familial cerebral amyloid angiopathy presenting as recurrent cerebral haemorrhage. J. Neurol. Sci. 55, 121–135 (1982).

    Article  CAS  Google Scholar 

  6. Bornebroek, M., Haan, J., Maat-Schieman, M.L., Van Duinen, S.G. & Roos, R.A. Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). I. A review of clinical, radiologic and genetic aspects. Brain. Pathol. 6, 111–114 (1996).

    Article  CAS  Google Scholar 

  7. Maat-Schieman, M.L., van Duinen, S.G., Bornebroek, M., Haan, J. & Roos, R.A. Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). II. A review of histopathological aspects. Brain. Pathol. 6, 115–120 (1996).

    Article  CAS  Google Scholar 

  8. Vinters, H.V. Cerebral amyloid angiopathy. A critical review. Stroke 18, 311–324 (1987).

    Article  CAS  Google Scholar 

  9. Greenberg, S.M. Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology 51, 690–694 (1998).

    Article  CAS  Google Scholar 

  10. Fraser, P.E. et al. Fibril formation by primate, rodent, and Dutch-hemorrhagic analogues of Alzheimer amyloid β-protein. Biochemistry 31, 10716–10723 (1992).

    Article  CAS  Google Scholar 

  11. De Jonghe, C. et al. Flemish and Dutch mutations in amyloid β precursor protein have different effects on amyloid β secretion. Neurobiol. Dis. 5, 281–286 (1998).

    Article  CAS  Google Scholar 

  12. Watson, D.J., Selkoe, D.J. & Teplow, D.B. Effects of the amyloid precursor protein Glu693ÆGln 'Dutch' mutation on the production and stability of amyloid β-protein. Biochem. J. 340 (Pt 3), 703–709 (1999).

    Article  CAS  Google Scholar 

  13. Monro, O.R. et al. Substitution at codon 22 reduces clearance of Alzheimer's amyloid-β peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood. Neurobiol. Aging 23, 405–412 (2002).

    Article  CAS  Google Scholar 

  14. Van Nostrand, W.E., Melchor, J.P. & Ruffini, L. Pathologic amyloid β-protein cell surface fibril assembly on cultured human cerebrovascular smooth muscle cells. J. Neurochem. 70, 216–223 (1998).

    Article  CAS  Google Scholar 

  15. Klafki, H.W., Wiltfang, J. & Staufenbiel, M. Electrophoretic separation of βA4 peptides (1–40) and (1–42). Anal. Biochem. 237, 24–29 (1996).

    Article  CAS  Google Scholar 

  16. Citron, M. et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat. Med. 3, 67–72 (1997).

    Article  CAS  Google Scholar 

  17. De Jonghe, C. et al. Evidence that Aβ42 plasma levels in presenilin-1 mutation carriers do not allow for prediction of their clinical phenotype. Neurobiol. Dis. 6, 280–287 (1999).

    Article  CAS  Google Scholar 

  18. Castano, E.M. et al. The length of amyloid-β in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Implications for the role of amyloid-β 1–42 in Alzheimer's disease. J. Biol. Chem. 271, 32185–32191 (1996).

    Article  CAS  Google Scholar 

  19. Prelli, F. et al. Expression of a normal and variant Alzheimer's β-protein gene in amyloid of hereditary cerebral hemorrhage, Dutch type: DNA and protein diagnostic assays. Biochem. Biophys. Res. Commun. 170, 301–307 (1990).

    Article  CAS  Google Scholar 

  20. Jankowsky, J.L. et al. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Hum. Mol. Genet. 13, 159–170 (2004).

    Article  CAS  Google Scholar 

  21. Johnson-Wood, K. et al. Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease. Proc. Natl. Acad. Sci. USA 94, 1550–1555 (1997).

    Article  CAS  Google Scholar 

  22. Richards, J.G. et al. PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation. J. Neurosci. 23, 8989–9003 (2003).

    Article  CAS  Google Scholar 

  23. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  24. Nilsberth, C. et al. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation. Nat. Neurosci. 4, 887–893 (2001).

    Article  CAS  Google Scholar 

  25. Tsubuki, S., Takaki, Y. & Saido, T.C. Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Aβ to physiologically relevant proteolytic degradation. Lancet 361, 1957–1958 (2003).

    Article  CAS  Google Scholar 

  26. Morelli, L. et al. Differential degradation of amyloid β genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme. J. Biol. Chem. 278, 23221–23226 (2003).

    Article  CAS  Google Scholar 

  27. Borchelt, D.R. et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939–945 (1997).

    Article  CAS  Google Scholar 

  28. Holcomb, L. et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 4, 97–100 (1998).

    Article  CAS  Google Scholar 

  29. Natte, R. et al. Ultrastructural evidence of early non-fibrillar Aβ42 in the capillary basement membrane of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type. Acta Neuropathol. (Berl.) 98, 577–582 (1999).

    Article  CAS  Google Scholar 

  30. Meyer-Luehmann, M. et al. Extracellular amyloid formation and associated pathology in neural grafts. Nat. Neurosci. 6, 370–377 (2003).

    Article  CAS  Google Scholar 

  31. Shibata, M. et al. Clearance of Alzheimer's amyloid-β(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Invest. 106, 1489–1499 (2000).

    Article  CAS  Google Scholar 

  32. Weller, R.O. et al. Cerebral amyloid angiopathy: amyloid β accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am. J. Pathol. 153, 725–733 (1998).

    Article  CAS  Google Scholar 

  33. Pfeifer, M. et al. Cerebral hemorrhage after passive anti-Aβ immunotherapy. Science 298, 1379 (2002).

    Article  CAS  Google Scholar 

  34. Das, P., Murphy, M.P., Younkin, L.H., Younkin, S.G. & Golde, T.E. Reduced effectiveness of Aβ1–42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiol. Aging 22, 721–727 (2001).

    Article  CAS  Google Scholar 

  35. Nicoll, J.A. et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat. Med. 9, 448–452 (2003).

    Article  CAS  Google Scholar 

  36. Koller, M.F. et al. Active immunization of mice with an Aβ-Hsp70 vaccine. Neurodegenerative Dis. 1, 20–28 (2004).

    Article  CAS  Google Scholar 

  37. Ferrer, I., Boada Rovira, M., Sánchez Guerra, M.L., Rey, M.J. & Costa-Jussá, F. Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer's disease. Brain Pathol. 14, 11–20 (2004).

    Article  CAS  Google Scholar 

  38. Natte, R. et al. Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann. Neurol. 50, 765–772 (2001).

    Article  CAS  Google Scholar 

  39. Greenberg, S.M. Cerebral amyloid angiopathy and dementia: two amyloids are worse than one. Neurology 58, 1587–1588 (2002).

    Article  Google Scholar 

  40. Christie, R., Yamada, M., Moskowitz, M. & Hyman, B. Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am. J. Pathol. 158, 1065–1071 (2001).

    Article  CAS  Google Scholar 

  41. Winkler, D.T. et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J. Neurosci. 21, 1619–1627 (2001).

    Article  CAS  Google Scholar 

  42. Calhoun, M.E. et al. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc. Natl. Acad. Sci. USA 96, 14088–14093 (1999).

    Article  CAS  Google Scholar 

  43. Van Dorpe, J. et al. Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons. Am. J. Pathol. 157, 1283–1298 (2000).

    Article  CAS  Google Scholar 

  44. Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA 94, 13287–13292 (1997).

    Article  CAS  Google Scholar 

  45. Bodendorf, U. et al. Expression of human β-secretase in the mouse brain increases the steady-state level of β-amyloid. J. Neurochem. 80, 799–806 (2002).

    Article  CAS  Google Scholar 

  46. Mehta, P.D. et al. Plasma and cerebrospinal fluid levels of amyloid β proteins 1–40 and 1–42 in Alzheimer disease. Arch. Neurol. 57, 100–105 (2000).

    Article  CAS  Google Scholar 

  47. Ohsawa, K., Imai, Y., Kanazawa, H., Sasaki, Y. & Kohsaka, S. Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J. Cell. Sci. 113 (Pt 17), 3073–3084 (2000).

    CAS  PubMed  Google Scholar 

  48. Janus, C. et al. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408, 979–982 (2000).

    Article  CAS  Google Scholar 

  49. Rozmahel, R. et al. Normal brain development in PS1 hypomorphic mice with markedly reduced γ-secretase cleavage of βAPP. Neurobiol. Aging 23, 187–194 (2002).

    Article  CAS  Google Scholar 

  50. Maat-Schieman, M.L., Yamaguchi, H., van Duinen, S.G., Natte, R. & Roos, R.A. Age-related plaque morphology and C-terminal heterogeneity of amyloid β in Dutch-type hereditary cerebral hemorrhage with amyloidosis. Acta Neuropathol. (Berl.) 99, 409–419 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank H. Widmer for experimental help; L. Walker, J. Ghiso and T. Saido for comments on this manuscript; and R. Nixon for support of the ELISA measurements. This work was supported by grants to M.J. from the Fritz Thyssen Foundation (Cologne, Germany), the EU under the sixth framework programme (priority: life sciences and health, LSHM-CT-2003-503330) and the Swiss National Science Foundation. This work was also supported by grants to P.M.M. from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.

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Authors and Affiliations

  1. Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, D-72076, Germany

    Martin C Herzig, Michelle Pfeifer, Esther Kohler & Mathias Jucker

  2. Department of Neuropathology, Institute of Pathology, University of Basel, Basel, CH-4003, Switzerland

    Martin C Herzig, David T Winkler, Patrick Burgermeister, Michelle Pfeifer, Esther Kohler & Mathias Jucker

  3. Nathan Kline Institute, New York University School of Medicine, Orangeburg, 10962, New York, USA

    Stephen D Schmidt & Paul M Mathews

  4. Novartis Institutes for Biomedical Research, Nervous Systems Research, Basel, CH-4002, Switzerland

    Simone Danner, Dorothee Abramowski, Christine Stürchler-Pierrat & Matthias Staufenbiel

  5. Institute of Laboratory Animal Science, University of Zürich, Zürich, CH-8057, Switzerland

    Kurt Bürki

  6. Departments of Pathology and Neurology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands

    Sjoerd G van Duinen & Marion L C Maat-Schieman

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Supplementary information

Supplementary Fig. 1

Intraneuronal Aβ in APPDutch and APPwt transgenic mice. NT12-immunostaining for Aβ (brown) in hippocampal CA1 neurons reveals intracellular human Aβ in a 29 month-old APPDutch (a) and a 24 month-old APPwt mouse (b), while no Aβ is detected in a 24 month-old non-transgenic control littermate (c). Bars are 20 μm (a–c). (JPG 56 kb)

Supplementary Table 1

Absolute Aβ levels in brains of pre-depositing and depositing transgenic mice, and HCHWA-D and AD patients. (PDF 19 kb)

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Herzig, M., Winkler, D., Burgermeister, P. et al. Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7, 954–960 (2004). https://doi.org/10.1038/nn1302

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