Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor
Open accessAbstract
Cerebrovascular deposition of amyloid beta-protein (Abeta) is a common pathological feature of Alzheimer's disease and related disorders. In particular, the Dutch E22Q and Iowa D23N mutations in Abeta cause familial cerebrovascular amyloidosis with abundant diffuse amyloid plaque deposits. Both of these charge-altering mutations enhance the fibrillogenic and pathogenic properties of Abeta in vitro. Here, we describe the generation of several transgenic mouse lines (Tg-SwDI) expressing human neuronal Abeta precursor protein (AbetaPP) harboring the Swedish K670N/M671L and vasculotropic Dutch/Iowa E693Q/D694N mutations under the control of the mouse Thy1.2 promoter. Tg-SwDI mice expressed transgenic human AbetaPP only in the brain, but at levels below those of endogenous mouse AbetaPP. Despite the paucity of human AbetaPP expression, quantitative enzyme-linked immunosorbent assay measurements revealed that Tg-SwDI mice developed early-onset and robust accumulation of Abeta in the brain with high association with isolated cerebral microvessels. Tg-SwDI mice exhibited striking perivascular/vascular Abeta deposits that markedly increased with age. The vascular Abeta accumulations were fibrillar, exhibiting strong thioflavin S staining, and occasionally presented signs of microhemorrhage. In addition, numerous largely diffuse, plaque-like structures were observed starting at 3 months of age. In vivo transport studies demonstrated that Dutch/Iowa mutant Abeta was more readily retained in the brain compared with wild-type Abeta. These results with Tg-SwDI mice demonstrate that overexpression of human AbetaPP is not required for early-onset and robust accumulation of both vascular and parenchymal Abeta in mouse brain.
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The Tg-SwDI transgenic mouse model is a particularly good model of CAA.
“For example, the Tg-SwDI transgenic mouse model is a particularly good model of CAA [29].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [29]
Tg-SwDI mice develop robust accumulation of fibrillar vascular Aβ and less prominent diffuse parenchymal plaques, starting at 3 months of age.
“Tg-SwDI mice develop robust accumulation of fibrillar vascular Aβ and less prominent diffuse parenchymal plaques, starting at 3 months of age [29](see Figure 2).”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [29]
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Studies on the first described Alzheimer's disease amyloid β mutant, the Dutch variant
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- Authors
- Davis, J., Xu, F., Deane, R., Romanov, G., Previti, M. L., Zeigler, K., Zlokovic, B. V., & Van Nostrand, W. E.
- Affiliations
- Stony Brook University (US)
- University of Rochester Medicine (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-05
- Volume
- 279
- Issue
- 19
- Pages
- 20296-20306
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2121820797
- Cited by
- 373
- References
- 45
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 13 · 2023: 19 · 2022: 16 · 2021: 16 · 2020: 32 · 2019: 16 · 2018: 15 · 2017: 14 · 2016: 25 · 2015: 21 · 2014: 15 · 2013: 21 · 2012: 18
- FWCI
- 8.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Vlaamse regering
- National Institute on Aging (AG16233)
- National Institute of Neurological Disorders and Stroke (R01NS036645, NS36645, NS34467)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- amyloid-beta, amyloid precursor protein, transgenic mice, amyloid plaques, microhemorrhages, Alzheimer's disease
- MeSH terms
- Animals, Brain, Enzyme-Linked Immunosorbent Assay, Genetic Vectors, Humans, Immunohistochemistry, Mice, Inbred C57BL, Mice, Transgenic, Microcirculation, Models, Genetic, Mutation, Peptides, Promoter Regions, Genetic, Thiazoles, Time Factors, Tissue Distribution, Immunoblotting, Amyloid beta-Peptides, DNA, Complementary, Transgenes, Mice, Benzothiazoles
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