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Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease

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Kisler, Kassandra, Nelson, Amy R., Montagne, Axel, Zlokovic, Berislav V.·2017·Nature Reviews Neuroscience
DOI 10.1038/nrn.2017.48PMC PMC5759779
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Abstract

Cerebral blood flow (CBF) regulation is essential for normal brain function. The mammalian brain has evolved a unique mechanism for CBF control known as neurovascular coupling. This mechanism ensures a rapid increase in the rate of CBF and oxygen delivery to activated brain structures. The neurovascular unit is composed of astrocytes, mural vascular smooth muscle cells and pericytes, and endothelia, and regulates neurovascular coupling. This Review article examines the cellular and molecular mechanisms within the neurovascular unit that contribute to CBF control, and neurovascular dysfunction in neurodegenerative disorders such as Alzheimer disease.

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  • CAA is caused by Aβ deposition in the vascular wall of small brain arteries and capillaries and develops as a result of an imbalance between Aβ production and clearance, particularly faulty transvascular and perivascular clearance of Aβ from the brain.

    “CAA is caused by A 𝛃 deposition in the vascular wall of small brain arteries and capillaries and develops as a result of an imbalance between A 𝛃 production and clearance, particularly faulty transvascular and perivascular clearance of A 𝛃 from the brain (318, 420, 581, 640).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [318]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • The pattern of cerebral blood vessels follows the major brain circuits tasked with sensation, memory, and motion, suggesting that the cerebrovascular system plays an important role in normal CNS functioning.

    “The pattern of cerebral blood vessels follows the major brain circuits tasked with sensation, memory, and motion suggesting that the cerebrovascular system plays an important role in normal CNS functioning (271, 318, 682).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [318]

    The Introduction (page unavailable) says brain function depends on healthy blood vessels and that blood flow increases in activated brain structures. It does not say that the anatomical pattern of cerebral vessels follows circuits for sensation, memory, and motion; that specific part of the claim is unsupported. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Focal blood-brain barrier breakdown in disease leads to perivascular accumulation of blood-derived toxic products and macromolecules, immune and/or inflammatory responses, vascular regression, and local cerebral blood flow reductions.

    “Second, focal BBB breakdown in the disease leads to perivascular accumulation of blood-derived toxic products and macromolecules, immune and/or inflammatory responses, vascular regression, and local CBF reductions (318, 693).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [318]

    The 'Neurovascular uncoupling in Alzheimer's disease' section identifies BBB breakdown and CBF reductions as early events in Alzheimer’s disease, but says how they relate to each other remains to be determined. The 'Capillary component' section says the intact BBB limits entry of macromolecules; the cited passages do not establish that focal BBB breakdown causes the full claimed sequence of perivascular accumulation, immune or inflammatory responses, vascular regression, and local CBF reductions. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Astrocytes, microglia, and endothelial cells establish tightly articulated physical and molecular interactions in a functionally integrated structure known as the gliovascular unit (GVU), through which many properties of the brain are maintained.

    “Astrocytes, microglia, and endothelial cells establish tightly articulated physical and molecular interactions [1, 2, 3, 4] in a functionally integrated structure known as the gliovascular unit (GVU) [5] through which many of the properties of the brain are maintained [3, 4].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [5]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Vascular risk factors and the allele APOE4 are the main factors of susceptibility identified to date for AD.

    “In particular, vascular risk factors and the allele APOE4 are the main factors of susceptibility identified to date [5, 58].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [5]

    In “Aβ-independent vascular changes in animal models” (page unavailable), the paper calls APOE4 the major genetic risk factor for AD and identifies hypertension as an AD risk factor. The broader “Alzheimer’s vascular dysfunction” section (page unavailable) also names vascular factors, but it does not establish that vascular risk factors and APOE4 together are the main susceptibility factors identified to date; it lists environmental and lifestyle factors as well. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Kisler, K., Nelson, A. R., Montagne, A., & Zlokovic, B. V.
ORCID
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2017-05-18
Volume
18
Issue
7
Pages
419-434
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/nrn.2017.48
PMC
PMC5759779
OpenAlex
W2616216465
Cited by
1,243
References
32
Citations by year
2026: 129 · 2025: 152 · 2024: 143 · 2023: 151 · 2022: 152 · 2021: 162 · 2020: 153 · 2019: 107 · 2018: 69 · 2017: 22 · 2013: 1
FWCI
9.26
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG023084, R01AG039452, P50AG005142, RF1AG039452, P01AG052350)
  • National Institute of Neurological Disorders and Stroke (R01NS100459, R01NS090904, R01NS034467)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
cerebral autoregulation, neurovascular coupling, neurovascular unit, Alzheimer's disease, neurovascular dysfunction, arterioles, capillaries, astrocytes, pericytes, vascular smooth muscle cells, endothelium, neurodegeneration, oxygen delivery
MeSH terms
Neurovascular Coupling, Alzheimer Disease, Brain, Cerebrovascular Circulation, Cerebrovascular Disorders, Humans, Models, Neurological

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