Cited by 373Alzheimer's disease research and treatmentsIntracerebral and Subarachnoid Hemorrhage ResearchBarrier Structure and Function Studies

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

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Davis, Judianne, Xu, Feng, Deane, Rashid, Romanov, Galina, Previti, Mary Lou, Zeigler, Kelly, Zlokovic, Berislav V., Van Nostrand, William E.·2004·Journal of Biological Chemistry

Abstract

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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Crossref · 10.1074/jbc.m312946200

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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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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
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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