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Cited by 179Neurological Disease Mechanisms and TreatmentsCerebrovascular and genetic disordersBarrier Structure and Function Studies

Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function

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Koizumi, Kenzo, Hattori, Yorito, Ahn, Sung Ji, Buendia, Izaskun, Ciacciarelli, Antonio, Uekawa, Ken, Wang, Gang, Hiller, Abigail +6 more·2018·Nature Communications
DOI 10.1038/s41467-018-06301-2PMC PMC6145902
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Abstract

The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.

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  • APOE4 reduces the density of blood vessels in these mice, thereby potentially impairing oxygen availability to neurons.

    “APOE4 also reduces the density of blood vessels in these mice, thereby potentially impairing oxygen availability to neurons188.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [188]

  • APOE4 has a negative impact on cerebral blood flow and neurovascular coupling; APOE4 mice show reduced cerebral blood flow both at baseline and in stimulus-evoked paradigms, relative to APOE3 mice.

    “APOE4 has a negative impact on cerebral blood flow and neurovascular coupling; APOE4 mice show reduced cerebral blood flow both at baseline and in stimulus-evoked paradigms, relative to APOE3 mice187–189.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [188]

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Cited by

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Authors
Koizumi, K., Hattori, Y., Ahn, S. J., Buendia, I., Ciacciarelli, A., Uekawa, K., Wang, G., Hiller, A., Zhao, L., Voss, H. U., Paul, S. M., Schaffer, C., Park, L., & Iadecola, C.
Affiliations
  • Weill Cornell Medicine (US)
  • Washington University in St. Louis (US)
  • Cornell University (US)
Corresponding author
  • Park, Laibaik
  • Iadecola, Costantino
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-09-19
Volume
9
Issue
1
Pages
3816-3816
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-06301-2
PMC
PMC6145902
OpenAlex
W2891667574
Cited by
179
References
12
Citations by year
2026: 22 · 2025: 30 · 2024: 25 · 2023: 21 · 2022: 21 · 2021: 21 · 2020: 24 · 2019: 13 · 2018: 1
FWCI
6.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (097805, 100447)
Topics
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
APOE ε4, apolipoprotein E, cerebral small vessel disease, vascular cognitive impairment, cerebral blood flow, neocortex, cerebral microvasculature, vessel density, white matter injury, corpus callosum, hypoxia, cerebral hypoperfusion, hypoxia-ischemia, cognitive impairment, targeted replacement mice
MeSH terms
Animals, Apolipoproteins E, Cerebrovascular Circulation, Cognition, Corpus Callosum, Humans, Metalloporphyrins, Mice, Inbred C57BL, Mice, Transgenic, Rest, Carotid Stenosis, Gene Targeting, White Matter

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