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Cited by 487Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Microvascular injury and blood–brain barrier leakage in Alzheimer's disease

Zipser, B.D., Johanson, C.E., Gonzalez, L., Berzin, T.M., Tavares, R., Hulette, C.M., Vitek, M.P., Hovanesian, V. +1 more·2007·Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2006.05.016
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Abstract

Thinning and discontinuities within the vascular basement membrane (VBM) are associated with leakage of the plasma protein prothrombin across the blood-brain barrier (BBB) in Alzheimer's disease (AD). Prothrombin immunohistochemistry and ELISA assays were performed on prefrontal cortex. In severe AD, prothrombin was localized within the wall and neuropil surrounding microvessels. Factor VIII staining in severe AD patients indicated that prothrombin leakage was associated with shrinkage of endothelial cells. ELISA revealed elevated prothrombin levels in prefrontal cortex AD cases that increased with the Braak stage (Control=1.39, I-II=1.76, III-IV=2.28, and V-VI=3.11 ng prothrombin/mg total protein). Comparing these four groups, there was a significant difference between control and Braak V-VI (p=0.0095) and also between Braak stages I-II and V-VI (p=0.0048). There was no significant difference in mean prothrombin levels when cases with versus without cerebral amyloid angiopathy (CAA) were compared (p-value=0.3627). When comparing AD patients by APOE genotype (ApoE3,3=2.00, ApoE3,4=2.49, and ApoE4,4=2.96 ng prothrombin/mg total protein) an analysis of variance indicated a difference between genotypes at the 10% significance level (p=0.0705). Tukey's test indicated a difference between the 3,3 and 4,4 groups (p=0.0607). These studies provide evidence that in advanced AD (Braak stage V-VI), plasma proteins like prothrombin can be found within the microvessel wall and surrounding neuropil, and that leakage of the blood-brain barrier may be more common in patients with at least one APOE4 allele.

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Crossref · 10.1016/j.neurobiolaging.2006.05.016

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  • These blood-derived proteins are often found colocalized with Aβ and are more pronounced in APOE4 carriers compared with noncarriers.

    “These blood-derived proteins are often found colocalized with A 𝛃 (267, 509, 527) and are more pronounced in APOE4 carriers compared with noncarriers (230, 267, 516, 691).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [691]

  • Human APOE4 carriers compared with non-carriers develop accelerated BBB breakdown and pericyte degeneration, early neurovascular dysfunction, impaired cerebrovascular reactivity, and diminished regional BBB uptake of glucose.

    “Human APOE4 carriers compared with non-carriers develop accelerated BBB breakdown and pericyte degeneration (229, 230, 267, 516, 691, 702), early neurovascular dysfunction (494, 531, 584), impaired cerebrovascular reactivity (227, 568), and diminished regional BBB uptake of glucose (457, 486).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [691]

  • Post mortem studies show vascular capillary leakages of blood-derived proteins in the prefrontal and entorhinal cortex and hippocampus of AD patients including perivascular accumulation of fibrin(ogen), thrombin, albumin, immunoglobulin G, and iron-containing proteins such as hemosiderin.

    “Post mortem studies show vascular capillary leakages of blood-derived proteins in the prefrontal and entorhinal cortex and hippocampus of AD patients including perivascular accumulation of fibrin(ogen), thrombin, albumin, immunoglobulin G (IgG), and iron-containing proteins such as hemosiderin (120, 125, 230, 267, 412, 509, 527, 691).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [691]

  • Impairments of the BBB have been observed in the context of neurodegenerative diseases.

    “impairments of the BBB have been observed in this context (Dickstein et al., 2006; Zipser et al., 2007; Lassman et al., 2012; Figure 2).”

    From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Zipser et al., 2007

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Authors
Zipser, B. D., Johanson, C. E., Gonzalez, L., Berzin, T. M., Tavares, R., Hulette, C. M., Vitek, M. P., Hovanesian, V., & Stopa, E. G.
Affiliations
  • Brown University (US)
  • Duke University (US)
Corresponding author
Stopa, E.G.
ORCID
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2007-07
Volume
28
Issue
7
Pages
977-986
ISSN
0197-4580 (ISSN-L)
DOI
10.1016/j.neurobiolaging.2006.05.016
OpenAlex
W1977960636
Cited by
487
References
63
Citations by year
2026: 15 · 2025: 23 · 2024: 27 · 2023: 35 · 2022: 29 · 2021: 48 · 2020: 32 · 2019: 26 · 2018: 26 · 2017: 27 · 2016: 29 · 2015: 19 · 2014: 28 · 2013: 26 · 2012: 21
FWCI
8.11
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neurobiology of Aging (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ag009301-08)
  • National Institute on Aging (AG05 128, AG-09301, P50AG005128, AG17975, R01AG017975)
  • National Institute of Neurological Disorders and Stroke (NS 27601, R01NS027601)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, blood-brain barrier disruption, microvascular damage, prothrombin, vascular basement membrane, cerebral amyloid angiopathy, Braak stages, APOE ε4, prefrontal cortex, factor VIII
MeSH terms
Adult, Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Apolipoproteins E, Basement Membrane, Blood-Brain Barrier, Cerebral Cortex, Cerebrovascular Disorders, Enzyme-Linked Immunosorbent Assay, Factor VIII, Female, Humans, Immunohistochemistry, Male, Middle Aged, Muscle, Smooth, Postmortem Changes, Prothrombin, Disease Progression

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