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Cited by 319Alzheimer's disease research and treatmentsBarrier Structure and Function StudiesNeuroinflammation and Neurodegeneration Mechanisms

Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease

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Paul, Justin, Strickland, Sidney, Melchor, Jerry P.·2007·The Journal of Experimental Medicine
DOI 10.1084/jem.20070304PMC PMC2118680
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Abstract

Cerebrovascular dysfunction contributes to the pathology and progression of Alzheimer's disease (AD), but the mechanisms are not completely understood. Using transgenic mouse models of AD (TgCRND8, PDAPP, and Tg2576), we evaluated blood–brain barrier damage and the role of fibrin and fibrinolysis in the progression of amyloid-β pathology. These mouse models showed age-dependent fibrin deposition coincident with areas of blood–brain barrier permeability as demonstrated by Evans blue extravasation. Three lines of evidence suggest that fibrin contributes to the pathology. First, AD mice with only one functional plasminogen gene, and therefore with reduced fibrinolysis, have increased neurovascular damage relative to AD mice. Conversely, AD mice with only one functional fibrinogen gene have decreased blood–brain barrier damage. Second, treatment of AD mice with the plasmin inhibitor tranexamic acid aggravated pathology, whereas removal of fibrinogen from the circulation of AD mice with ancrod treatment attenuated measures of neuroinflammation and vascular pathology. Third, pretreatment with ancrod reduced the increased pathology from plasmin inhibition. These results suggest that fibrin is a mediator of inflammation and may impede the reparative process for neurovascular damage in AD. Fibrin and the mechanisms involved in its accumulation and clearance may present novel therapeutic targets in slowing the progression of AD.

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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 [467]

    The Results section reports increased BBB permeability in three APP transgenic models carrying familial AD mutations at 6 and 12 months. It does not establish that disruption precedes Aβ accumulation or CAA; the Discussion instead suggests that increased Aβ likely causes the initial vascular insult. The Animals section also reports memory defects in TgCRND8 mice as early as 3 months, before the paper's BBB measurements. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • 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 [467]

    The Results section reports increased blood–brain barrier permeability in Tg2576 and two other mouse models at 6 and 12 months, supporting the BBB-damage portion of the claim. It does not establish breakdown beginning at 1–3 months or preceding Aβ deposition and CAA. The Animals section says Tg2576 mice develop cognitive deficits by 9 months, rather than placing their onset at 10–12 months. Page numbers were unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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 [467]

    The Results section (pages not provided) reports increased blood–brain barrier permeability in three APP-transgenic mouse models and shows Evans blue–bound albumin outside damaged vessels. It also describes reduced endothelial-marker staining in TgCRND8 mice. The cited paper does not establish the sentence’s other listed features—microbleeds, impaired Aβ clearance at the BBB, loss of VSMCs or pericytes, or CAA—in these mice. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Depleting fibrinogen and/or preventing its accumulation in the brain with ancrod attenuated both neuroinflammation and vascular pathology in Alzheimer's disease mice and in a multiple sclerosis model.

    “Depleting fibrinogen and/or preventing its accumulation in the brain, as for example with ancrod, a defibrinogenating agent, attenuated both neuroinflammation and vascular pathology in AD mice (467) and in an MS model (132).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [467]

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Cited by

Sorted by citations

Authors
Paul, J., Strickland, S., & Melchor, J. P.
Affiliations
Rockefeller University (US)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2007-07-30
Volume
204
Issue
8
Pages
1999-2008
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20070304
PMC
PMC2118680
OpenAlex
W2152601025
Cited by
319
References
6
Citations by year
2026: 10 · 2025: 15 · 2024: 15 · 2023: 22 · 2022: 21 · 2021: 16 · 2020: 23 · 2019: 17 · 2018: 24 · 2017: 19 · 2016: 19 · 2015: 20 · 2014: 26 · 2013: 12 · 2012: 21
FWCI
4.45
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (AG20901, F32AG020901)
  • National Institute of General Medical Sciences (GM66699, GM 07739, T32GM066699, T32GM007739)
  • National Institute of Neurological Disorders and Stroke (R01NS050537, NS50537)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, fibrin deposition, fibrinolysis, blood-brain barrier permeability, neurovascular injury, neuroinflammation, amyloid-beta pathology, plasminogen, fibrinogen, tranexamic acid, ancrod, cerebrovascular dysfunction, TgCRND8 mice, PDAPP mice, Tg2576 mice
MeSH terms
Alzheimer Disease, Animals, Blood-Brain Barrier, Disease Models, Animal, Fibrin, Fibrinogen, Inflammation, Mice, Transgenic, Models, Biological, Permeability, Plasminogen, Tranexamic Acid, Disease Progression, Mice

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