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Cited by 872Barrier Structure and Function StudiesDrug Transport and Resistance MechanismsCerebrospinal fluid and hydrocephalus

Functional morphology of the blood–brain barrier in health and disease

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Liebner, Stefan, Dijkhuizen, Rick M., Reiss, Yvonne, Plate, Karl H., Agalliu, Dritan, Constantin, Gabriela·2018·Acta Neuropathologica
DOI 10.1007/s00401-018-1815-1PMC PMC6781630
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Abstract

The adult quiescent blood-brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at the same time. In the past decade, there has been considerable progress in understanding not only the molecular pathways involved in BBB development, but also BBB breakdown in neurological diseases. Specifically, the Wnt/β-catenin, retinoic acid and sonic hedgehog pathways moved into the focus of BBB research. Moreover, angiopoietin/Tie2 signalling that is linked to angiogenic processes has gained attention in the BBB field. Blood vessels play an essential role in initiation and progression of many diseases, including inflammation outside the central nervous system (CNS). Therefore, the potential influence of CNS blood vessels in neurological diseases associated with BBB alterations or neuroinflammation has become a major focus of current research to understand their contribution to pathogenesis. Moreover, the BBB remains a major obstacle to pharmaceutical intervention in the CNS. The complications may either be expressed by inadequate therapeutic delivery like in brain tumours, or by poor delivery of the drug across the BBB and ineffective bioavailability. In this review, we initially describe the cellular and molecular components that contribute to the steady state of the healthy BBB. We then discuss BBB alterations in ischaemic stroke, primary and metastatic brain tumour, chronic inflammation and Alzheimer's disease. Throughout the review, we highlight common mechanisms of BBB abnormalities among these diseases, in particular the contribution of neuroinflammation to BBB dysfunction and disease progression, and emphasise unique aspects of BBB alteration in certain diseases such as brain tumours. Moreover, this review highlights novel strategies to monitor BBB function by non-invasive imaging techniques focussing on ischaemic stroke, as well as novel ways to modulate BBB permeability and function to promote treatment of brain tumours, inflammation and Alzheimer's disease. In conclusion, a deep understanding of signals that maintain the healthy BBB and promote fluctuations in BBB permeability in disease states will be key to elucidate disease mechanisms and to identify potential targets for diagnostics and therapeutic modulation of the BBB.

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  • In early Alzheimer's disease, transporter dysfunction, specifically reduced expression of GLUT1 and LRP1, occurs prior to brain atrophy.

    “Another early-stage feature is transporter dysfunction, specifically reduced expression of GLUT1 and LRP1 prior to brain atrophy [48, 49].”

    From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [48]

    The “Blood–brain barrier pathology in Alzheimer’s disease” section (page unavailable) reports reduced GLUT1 and LRP1 expression in AD patients. It says disrupted glucose uptake in mild cognitive impairment may precede neurodegeneration, but does not establish that reduced expression of both transporters occurs before brain atrophy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In advanced Alzheimer's disease, blood-brain barrier alterations are marked by progressive loss of tight junction proteins, namely decreased expression of occludin, claudin-5, and ZO-1.

    “In advanced AD, BBB alterations are marked by the progressive loss of TJ proteins—namely, decreased expression of occludin, claudin-5, and ZO-1 [48, 49].”

    From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [48]

    The “Blood–brain barrier pathology in Alzheimer’s disease” section (page not available in our copy) reports reduced tight-junction protein expression in patients with capillary cerebral amyloid angiopathy and describes tight-junction disruption in AD. It does not establish progressive loss specifically in advanced AD or report decreased expression of occludin, claudin-5, and ZO-1 individually; those proteins are named in the separate steady-state endothelial-cell section. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In advanced Alzheimer's disease, there is increased penetration of immune cells, including neutrophils, macrophages, and T lymphocytes, into the brain parenchyma.

    “There is also increased penetration of immune cells, including neutrophils, macrophages, and T lymphocytes, into the brain parenchyma [48, 49].”

    From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [48]

    The “Blood–brain barrier pathology in Alzheimer’s disease” section (page unavailable) reports neutrophil and T-cell migration into the parenchyma of AD patients. It discusses monocytes entering the brains of AD-like mice, but does not establish macrophage penetration into the human brain parenchyma or limit the finding to advanced AD. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Liebner, S., Dijkhuizen, R. M., Reiss, Y., Plate, K. H., Agalliu, D., & Constantin, G.
Affiliations
  • German Centre for Cardiovascular Research (DE)
  • Utrecht University (NL)
  • German Cancer Research Center (DE)
  • Columbia University Irving Medical Center (US)
  • University of Verona (IT)
Corresponding author
Liebner, Stefan
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2018-02-06
Volume
135
Issue
3
Pages
311-336
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-018-1815-1
PMC
PMC6781630
OpenAlex
W2791041386
Cited by
872
References
19
Citations by year
2026: 87 · 2025: 109 · 2024: 122 · 2023: 132 · 2022: 123 · 2021: 121 · 2020: 93 · 2019: 60 · 2018: 25
FWCI
7.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • Deutsche Forschungsgemeinschaft (LI911/5-1, INST 35/869, SFB/TR23 C1, ECCPS)
  • H2020 Marie Skłodowska-Curie Actions (H2020-MSCA-ITN-2015)
  • Netherlands Organization for Scientific Research (016.130.662)
  • EU Joint Programme–Neurodegenerative Disease Research (733051067)
  • Hartstichting (CVON2015-01)
  • German Cancer Consortium (DKTK)
  • DZHK (Column B)
  • National Institutes of Health ((#R01 HL116995, #R56 MH109987, #R01 MH112849)
  • National Multiple Sclerosis Society (NMSS #RG4673A1/1)
  • Leducq Foundation
  • European Research Council (695714, 693606)
  • American Drug Discovery Foundation
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
Keywords
blood-brain barrier, blood-brain barrier permeability, neurovascular unit, endothelial cells, pericytes, astrocytes, microglia, Wnt/β-catenin signaling, retinoic acid signaling, Sonic hedgehog signaling, neuroinflammation, ischemic stroke, brain tumors, brain metastases, Alzheimer's disease, chronic inflammation, brain drug delivery
MeSH terms
Animals, Blood-Brain Barrier, Humans

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