Blood—Brain Barrier Permeability Precedes Senile Plaque Formation in an Alzheimer Disease Model
Abstract
Objective: To establish the generality of cerebrovascular pathology frequently observed with Alzheimer disease, we have assessed blood‐brain barrier (BBB) integrity using the Alzheimer disease model Tg2576 mice in which cognitive deficits and neuritic plaque formation develop around 10–12 months of age. Methods: We assessed BBB integrity using well‐established methods involving albumin and Evans blue uptake and introduce the use of a novel perfusion protocol using succinimidyl ester of carboxyfluorescein diacetate. Results: BBB permeability is increased in the cerebral cortex of 10‐month‐old Tg2576 mice preceding Alzheimer disease pathology presentation. Furthermore, when compared with their nontransgenic littermates, 4‐month‐old Tg2576 mice exhibit compromised BBB integrity in some areas of the cerebral cortex. An age‐related increase in albumin uptake by the brains of Tg2576 mice, compared with nontransgenic mice, was also observed. These findings were supported by quantitative Evans blue analysis (p = 0.07, two‐way analysis of variance). Conclusion: A breakdown of BBB was evident in young 4‐ to 10‐month‐old Tg2576 mice. Compromised barrier function could explain the mechanisms of Aβ entry into the brain observed in experimental Alzheimer disease vaccination models. Such structural changes to the BBB caused by elevated Aβ could play a central role in Alzheimer disease development and might define an early point of intervention for designing effective therapy against the disease.
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BBB disruption develops early in APP transgenic models carrying human ADAD mutations before Aβ accumulation, CAA, and behavioral deficits.
“Additionally, laboratory studies tell us that BBB disruption develops early in APP transgenic models carrying human ADADmutations (467, 513, 606) before A 𝛃 accumulation, CAA, and behavioral deficits (151, 336, 606, 638)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [606]
Progressive BBB breakdown develops early in APP Sw/0 mice beginning at 1-3 months of age before Aβ deposition, CAA, and behavioral memory recognition deficits that are observed beginning at 10-12 months of age.
“Some studies in transgenic murine models have examined the temporal sequence of appearance of different pathologies, revealing that progressive BBB breakdown develops early in APP Sw/0 mice beginning at 1-3 mo of age (467, 513, 606) before A 𝛃 deposition, CAA, and behavioral memory recognition deficits that are observed beginning at 10-12 mo of age (151, 336, 606, 638).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [606]
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 [606]
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References 28 · Cited by 351
- Authors
- UJIIE, M., DICKSTEIN, D. L., CARLOW, D. A., & JEFFERIES, W. A.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- JEFFERIES, WILFRED A.
- Venue
- Microcirculation
- Publisher
- Wiley
- Published
- 2003-12
- Volume
- 10
- Issue
- 6
- Pages
- 463-470
- ISSN
- 1073-9688 (ISSN-L)
- 1549-8719
- OpenAlex
- W2136838641
- Cited by
- 351
- References
- 28
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 11 · 2023: 16 · 2022: 14 · 2021: 20 · 2020: 20 · 2019: 19 · 2018: 22 · 2017: 17 · 2016: 20 · 2015: 14 · 2014: 33 · 2013: 20 · 2012: 18
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Microcirculation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- blood-brain barrier permeability, Alzheimer's disease, Tg2576 mice, amyloid plaques, cerebral cortex, albumin uptake, Evans blue, amyloid-beta, cerebrovascular pathology
- MeSH terms
- Aging, Albumins, Alzheimer Disease, Analysis of Variance, Animals, Blood-Brain Barrier, Capillary Permeability, Cerebral Cortex, Disease Models, Animal, Evans Blue, Mice, Inbred C57BL, Time Factors, Animals, Genetically Modified, Mice, Plaque, Amyloid
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