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Cited by 40Neurological Disease Mechanisms and TreatmentsBarrier Structure and Function StudiesAlzheimer's disease research and treatments

Assessment of neurovascular coupling and cortical spreading depression in mixed mouse models of atherosclerosis and Alzheimer’s disease

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Shabir, Osman, Pendry, Ben, Lee, Llywelyn, Eyre, Beth, Sharp, Paul S, Rebollar, Monica A, Drew, David, Howarth, Clare +4 more·2022·eLife
DOI 10.7554/elife.68242PMC PMC8752088

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Abstract

Neurovascular coupling is a critical brain mechanism whereby changes to blood flow accompany localised neural activity. The breakdown of neurovascular coupling is linked to the development and progression of several neurological conditions including dementia. In this study, we examined cortical haemodynamics in mouse preparations that modelled Alzheimer’s disease (J20-AD) and atherosclerosis (PCSK9-ATH) between 9 and 12 m of age. We report novel findings with atherosclerosis where neurovascular decline is characterised by significantly reduced blood volume, altered levels of oxyhaemoglobin and deoxyhaemoglobin, in addition to global neuroinflammation. In the comorbid mixed model (J20-PCSK9-MIX), we report a 3 x increase in hippocampal amyloid-beta plaques. A key finding was that cortical spreading depression (CSD) due to electrode insertion into the brain was worse in the diseased animals and led to a prolonged period of hypoxia. These findings suggest that systemic atherosclerosis can be detrimental to neurovascular health and that having cardiovascular comorbidities can exacerbate pre-existing Alzheimer’s-related amyloid-plaques.

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  • Increased brain expression of PCSK9 induced atherosclerosis, brain hypoxia, and Aβ deposits in the brain.

    “increased the brain expression of PCSK9 induced atherosclerosis, brain hypoxia and Aβ deposits in the brain [22].”

    From Blood PCSK9 Impacts Alzheimer's Disease Risk in an <i>APOE</i> Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [22]

    Materials and methods (Animals; page unavailable) describes atherosclerosis induced by intravenous PCSK9-vector injection together with a Western diet, not by demonstrated increased PCSK9 expression in the brain. Results reports threefold more hippocampal Aβ plaques in the mixed model, while Discussion says the mice could be hypoxic rather than establishing brain hypoxia. (LLM, conf=0.88)

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Authors
Shabir, O., Pendry, B., Lee, L., Eyre, B., Sharp, P. S., Rebollar, M. A., Drew, D., Howarth, C., Heath, P. R., Wharton, S. B., Francis, S. E., & Berwick, J.
Affiliations
  • Royal Hallamshire Hospital (GB)
  • University of Sheffield (GB)
  • Medicines Discovery Catapult (GB)
Corresponding author
  • Shabir, Osman
  • Berwick, Jason
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2022-01-11
Volume
11
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.68242
PMC
PMC8752088
OpenAlex
W4206066763
Cited by
40
References
39
Citations by year
2026: 7 · 2025: 12 · 2024: 7 · 2023: 8 · 2022: 4 · 2021: 2
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of Sheffield (Neuroimaging in Cardiovascular Disease (NICAD) network scholarship)
  • British Heart Foundation (PG/13/55/30365)
  • Wellcome Trust (105586/Z/14/Z, Sir Henry Dale Fellowship)
  • Royal Society (Sir Henry Dale Fellowship)
  • Alzheimer’s Research UK (R/153749-12-1)
  • Consejo Nacional de Ciencia y Tecnología
Topics
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
neurovascular coupling, cortical spreading depression, atherosclerosis, Alzheimer's disease, cerebral hemodynamics, blood volume, oxyhemoglobin, deoxyhemoglobin, neuroinflammation, amyloid plaques, hippocampus, hypoxia, cardiovascular comorbidity, mouse model
MeSH terms
Neurovascular Coupling, Alzheimer Disease, Animals, Brain, Cerebrovascular Circulation, Disease Models, Animal, Hemodynamics, Male, Mice, Inbred C57BL, Cortical Spreading Depression, Amyloid beta-Protein Precursor, Atherosclerosis, Mice

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