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APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice

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Bonnar, Orla, Shaw, Kira, Anderle, Silvia, Grijseels, Dori M, Clarke, Devin, Bell, Laura, King, Sarah L, Hall, Catherine N·2023·Journal of Cerebral Blood Flow & Metabolism
DOI 10.1177/0271678x231172842PMC PMC10676141

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Abstract

Vascular factors are known to be early and important players in Alzheimer’s disease (AD) development, however the role of the ε4 allele of the Apolipoprotein (APOE) gene (a risk factor for developing AD) remains unclear. APOE4 genotype is associated with early and severe neocortical vascular deficits in anaesthetised mice, but in humans, vascular and cognitive dysfunction are focused on the hippocampal formation and appear later. How APOE4 might interact with the vasculature to confer AD risk during the preclinical phase represents a gap in existing knowledge. To avoid potential confounds of anaesthesia and to explore regions most relevant for human disease, we studied the visual cortex and hippocampus of awake APOE3 and APOE4-TR mice using 2-photon microscopy of neurons and blood vessels. We found mild vascular deficits: vascular density and functional hyperaemia were unaffected in APOE4 mice, and neuronal or vascular function did not decrease up to late middle-age. Instead, vascular responsiveness was lower, arteriole vasomotion was reduced and neuronal calcium signals during visual stimulation were increased. This suggests that, alone, APOE4 expression is not catastrophic but stably alters neurovascular physiology. We suggest this state makes APOE4 carriers more sensitive to subsequent insults such as injury or beta amyloid accumulation.

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  • 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 [187]

    The Results sections (page unavailable) support mildly impaired neurovascular coupling: some APOE4 vessels responded less reliably to neuronal activity. But they report no genotype difference in baseline blood-flow measures or in overall cerebral blood-flow responses to visual stimulation in awake mice. The Introduction describes reduced baseline and stimulus-induced flow in earlier studies of anaesthetised mice, not as this study’s finding. (LLM, conf=0.90)

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Cited by

Sorted by citations

Authors
Bonnar, O., Shaw, K., Anderle, S., Grijseels, D. M., Clarke, D., Bell, L., King, S. L., & Hall, C. N.
Affiliations
University of Sussex (GB)
Corresponding author
Hall, Catherine N
ORCID
Venue
Journal of Cerebral Blood Flow & Metabolism
Publisher
SAGE Publications
Published
2023-06-23
Volume
43
Issue
11
Pages
1826-1841
ISSN
  • 0271-678X (ISSN-L)
  • 1559-7016
DOI
10.1177/0271678x231172842
PMC
PMC10676141
OpenAlex
W4381715676
Cited by
8
References
8
Citations by year
2026: 2 · 2025: 3 · 2024: 3
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cerebral Blood Flow & Metabolism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
Funders
  • Wellcome Trust
  • Alzheimer's Society
  • Academy of Medical Sciences (SBF001\1012)
  • Medical Research Council (MC_PC_15071, MR/X010678/1, MR/S026495/1)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
APOE ε4, apolipoprotein E, Alzheimer's disease risk, neurovascular coupling, visual cortex, hippocampus, functional hyperaemia, vessel density, preclinical Alzheimer's disease, vascular dysfunction
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Hippocampus, Humans, Mice, Transgenic, Middle Aged, Visual Cortex, Wakefulness, Mice, Apolipoprotein E3, Apolipoprotein E4

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