Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis
Open accessAbstract
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-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 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 Abeta 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 Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.
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Shifting the Aβ42/Aβ40 ratio in APP mutant transgenic mice under a neuron-specific promoter shifts parenchymal Aβ42 plaques to vascular Aβ40 amyloid.
“An intriguing study showed that shifting the ratio of Aβ42 to Aβ40 in APP mutant transgenic mice under a neuron-specific promoter shifted the preponderance of parenychmal Aβ42 plaques to vascular Aβ40 amyloid [73].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [73]
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Self-citation
- Authors
- Herzig, M. C., Winkler, D. T., Burgermeister, P., Pfeifer, M., Kohler, E., Schmidt, S. D., Danner, S., Abramowski, D., Stürchler-Pierrat, C., Bürki, K., van Duinen, S. G., Maat-Schieman, M. L. C., Staufenbiel, M., Mathews, P. M., & Jucker, M.
- Affiliations
- Hertie Institute for Clinical Brain Research (DE)
- University of Basel (CH)
- New York University (US)
- Novartis (Switzerland) (CH)
- University of Zurich (CH)
- Corresponding author
- Jucker, Mathias
- Venue
- Nature Neuroscience
- Published
- 2004-08-15
- Volume
- 7
- Issue
- 9
- Pages
- 954-960
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2126019582
- Cited by
- 391
- References
- 52
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 9 · 2023: 15 · 2022: 13 · 2021: 14 · 2020: 19 · 2019: 15 · 2018: 14 · 2017: 15 · 2016: 17 · 2015: 12 · 2014: 17 · 2013: 17 · 2012: 32
- FWCI
- 12.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fritz Thyssen Stiftung
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- hereditary cerebral hemorrhage with amyloidosis-Dutch type, cerebral amyloid angiopathy, amyloid-beta, presenilin 1, smooth muscle cell degeneration, neuroinflammation, cerebral hemorrhage, Alzheimer's disease, anti-amyloid therapy
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Amyloidosis, Animals, Blood Vessels, Brain, Cerebral Hemorrhage, Cerebrovascular Circulation, Disease Models, Animal, Encephalitis, Enzyme-Linked Immunosorbent Assay, Glutamine, Humans, Immunohistochemistry, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Middle Aged, Mutation, Peptide Fragments, Pia Mater, Postmortem Changes, Blotting, Western, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, In Situ Hybridization, Glutamic Acid, Thy-1 Antigens, Mice
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