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Cited by 406Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

A leaky blood–brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain

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Ryu, Jae K., McLarnon, James G.·2009·Journal of Cellular and Molecular Medicine
DOI 10.1111/j.1582-4934.2008.00434.xPMC PMC4498946
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Abstract

This study has used immunohistochemical examination of tissue obtained from Alzheimer’s disease (AD) brains and rat hippocampus injected with Aβ 1‐42 peptide to determine effects of induced inflammatory reactivity on integrity of blood–brain barrier (BBB) and viability of neurons. Tissue from AD, but not non‐demented, brains exhibited a diffuse pattern of staining for fibrinogen and immunoglobulin (IgG) indicative of BBB leakiness with considerable fibrinogen immunoreactivity (ir) appearing in association with Aβ deposits. Immunostaining for the endothelial cell specific glycoprotein, von Willebrand factor, showed morphological evidence for altered blood vessels in AD tissue. AD brains also demonstrated extensive areas of fibrinogen ir in association with microglial reactivity. In vivo, intra‐hippocampal injection of Aβ 1‐42 caused time‐dependent (1–7 days after injection) increases in double staining of fibrinogen with areas of microgliosis. Two independent pharmacological strategies were employed to examine how Aβ 1‐42 stimulation (7 days injection) may be linked to neurodegeneration. The defibrinogenating compound, ancrod, reduced inflammatory reactivity, levels of parenchymal fibrinogen and IgG, and was neuroprotective. These results prompted use of Aβ 1‐42 plus fibrinogen as a novel in vivo inflammatory stimulus and this combination significantly enhanced inflammatory reactivity, vascular perturbations and neuronal damage compared to Aβ 1‐42 alone. A second approach, using anti‐Mac‐1 (antibody for antigen CD11b) to block activation of microglia, was highly effective in attenuating effects of Aβ 1‐42 plus fibrinogen amplification of inflammatory and vascular responses and conferred significant neuroprotection. The overall findings from study of AD tissue and in vivo in Aβ 1‐42 and Aβ 1‐42 plus fibrinogen stimulated rat hippocampus suggest microglial responses to promote increased extravasation of blood protein as a critical component in amplifying inflammatory reactivity and causing neuronal damage in inflamed AD brain.

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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 [509]

    The Results (Patterns of fibrinogen staining in AD and ND brain sections; page unavailable) report fibrinogen near Aβ plaques in AD tissue, while also noting regions without evident co-localization. The paper does not report a comparison between APOE4 carriers and noncarriers, so it does not support that part of the claim. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • 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 [509]

    The Results (no page number supplied) show fibrinogen outside vessels and increased IgG staining in the entorhinal cortex of AD brain tissue, supporting vascular leakage there. The paper does not report the claimed leakage in the prefrontal cortex or human hippocampus, or perivascular accumulation of thrombin, albumin, or hemosiderin. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In patients and mouse models of AD, fibrinogen extravasates in the brain at sites of impaired blood-brain barrier integrity and cerebrovascular dysfunction, which are early features of AD pathogenesis.

    “In patients and mouse models of AD, fibrinogen extravasates in the brain at sites of impaired blood-brain barrier integrity and cerebrovascular dysfunction, which are early features of AD pathogenesis.21,39-42”

    From Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models (2024) · cites this paper as [42]

    The Introduction reports fibrinogen extravasation through a weakened blood–brain barrier in AD brains and fibrin deposition with damaged vasculature in transgenic mouse models. The Discussion describes extravascular fibrinogen near abnormal vessels in AD tissue. Neither passage establishes that blood–brain barrier impairment or cerebrovascular dysfunction is an early feature of AD pathogenesis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 33

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Authors
Ryu, J. K., & McLarnon, J. G.
Affiliations
University of British Columbia (CA)
Corresponding author
McLarnon, James G.
ORCID
Venue
Journal of Cellular and Molecular Medicine
Publisher
Wiley
Published
2009-09
Volume
13
Issue
9a
Pages
2911-2925
ISSN
  • 1582-1838 (ISSN-L)
  • 1582-4934
DOI
10.1111/j.1582-4934.2008.00434.x
PMC
PMC4498946
OpenAlex
W2029881431
Cited by
406
References
0
Citations by year
2026: 21 · 2025: 23 · 2024: 35 · 2023: 27 · 2022: 31 · 2021: 45 · 2020: 43 · 2019: 26 · 2018: 28 · 2017: 20 · 2016: 15 · 2015: 19 · 2014: 20 · 2013: 13 · 2012: 11
FWCI
6.38
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Cellular and Molecular Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • Fondation pour la Recherche sur Alzheimer
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, fibrinogen, microglial activation, amyloid-beta 42, neuroinflammation, ancrod, defibrinogenation, von Willebrand factor, hippocampus, neuroprotection, neuronal injury
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Ancrod, Animals, Astrocytes, Blood Vessels, Blood-Brain Barrier, Brain, Dementia, Fibrinogen, Fluorescence, Humans, Inflammation, Male, Middle Aged, Peptide Fragments, Permeability, von Willebrand Factor, Macrophage-1 Antigen, Amyloid beta-Peptides, Rats, Sprague-Dawley, Microglia, Rats

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