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Cited by 28Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsNanoparticle-Based Drug Delivery

Cerebral Vascular Leak in a Mouse Model of Amyloid Neuropathology

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Tanifum, Eric A, Starosolski, Zbigniew A, Fowler, Stephanie W, Jankowsky, Joanna L, Annapragada, Ananth V·2014·Journal of Cerebral Blood Flow & Metabolism
DOI 10.1038/jcbfm.2014.125PMC PMC4269723
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Abstract

In Alzheimer's disease (AD), there is increasing evidence of blood–brain barrier (BBB) compromise, usually observed as ‘microbleeds’ correlated with amyloid plaque deposition and apoE- ε4 status, raising the possibility of nanotherapeutic delivery. Molecular probes have been used to study neurovascular leak, but this approach does not adequately estimate vascular permeability of nanoparticles. We therefore characterized cerebrovascular leaks in live APP+ transgenic animals using a long circulating ~100 nm nanoparticle computed tomography (CT) contrast agent probe. Active leaks fell into four categories: (1) around the dorsomedial cerebellar artery (DMCA), (2) around other major vessels, (3) nodular leaks in the cerebral cortex, and (4) diffuse leaks. Cortical leaks were uniformly more frequent in the transgenic animals than in age-matched controls. Leaks around vessels other than the DMCA were more frequent in older transgenics compared with younger ones. All other leaks were equally prevalent across genotypes independent of age. Ten days after injection, 4 to 5 μg of the dose was estimated to be present in the brain, roughly a half of which was in locations other than the leaky choroid plexus, and associated with amyloid deposition in older animals. These results suggest that amyloid deposition and age increase delivery of nanoparticle-borne reagents to the brain, in therapeutically relevant amounts.

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  • Transgenic mice expressing different human APP mutations exhibit pronounced vascular pathology including severe BBB permeability changes, microbleeds, BBB leakages of blood-derived molecules, impaired Aβ clearance at the BBB, endothelial cell degeneration, loss of VSMCs and pericytes, and CAA.

    “Similar to humans, transgenic mice expressing different human APP mutations exhibit pronounced vascular pathology including severe BBB permeability changes (322, 467, 579, 606), microbleeds (56, 321, 322, 336, 579), BBB leakages of blood-derived molecules (109, 331, 336, 467, 513), impaired A 𝛃 clearance at the BBB (57, 137, 464, 512), endothelial cell degeneration (336, 513), loss of VSMCs (336,”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [579]

    The Results and Discussion report more frequent cortical vascular leaks in APP+ mice than in controls, along with hemosiderin deposits consistent with microbleeds. They do not establish broadly severe BBB permeability changes: the Results describe the bleeds as generally small and infrequent, and find a genotype difference in leak volume only for spherical cortical leaks. The cited paper is offered for the permeability and microbleed portions of the sentence, not its other listed pathologies. (LLM, conf=0.86)

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Cited by

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Authors
Tanifum, E. A., Starosolski, Z. A., Fowler, S. W., Jankowsky, J. L., & Annapragada, A. V.
Affiliations
  • Texas Children's Hospital (US)
  • Silesian University of Technology (PL)
  • Baylor College of Medicine (US)
Corresponding author
Annapragada, Ananth V
ORCID
Venue
Journal of Cerebral Blood Flow & Metabolism
Publisher
SAGE Publications
Published
2014-07-23
Volume
34
Issue
10
Pages
1646-1654
ISSN
  • 0271-678X (ISSN-L)
  • 1559-7016
DOI
10.1038/jcbfm.2014.125
PMC
PMC4269723
OpenAlex
W2064891058
Cited by
28
References
2
Citations by year
2026: 2 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 7 · 2015: 4
FWCI
2.08
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Dental and Craniofacial Research (R01DE024392)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
blood-brain barrier permeability, Alzheimer's disease, amyloid plaques, APP transgenic mice, nanoparticle delivery, live imaging, choroid plexus, nanotherapeutics
MeSH terms
Amyloid, Animals, Blood-Brain Barrier, Brain, Cerebral Arteries, Contrast Media, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Tomography, X-Ray Computed, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Mice, Nanoparticles

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