APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice

Abstract Reduced cerebral blood flow occurs early in the development of Alzheimer’s disease (AD), but the factors producing this reduction are unknown. Here, we ask whether genetic and lifestyle risk factors for AD—the ε4 allele of the Apolipoprotein (APOE) gene, and physical activity—can together p...

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Main Authors: Silvia Anderle, Orla Bonnar, Joseph Henderson, Kira Shaw, Andre M. Chagas, Letitia McMullan, Alexandra Webber, Kirsty McGowan, Sarah L. King, Catherine N. Hall
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Communications Biology
Online Access:https://doi.org/10.1038/s42003-025-07585-z
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author Silvia Anderle
Orla Bonnar
Joseph Henderson
Kira Shaw
Andre M. Chagas
Letitia McMullan
Alexandra Webber
Kirsty McGowan
Sarah L. King
Catherine N. Hall
author_facet Silvia Anderle
Orla Bonnar
Joseph Henderson
Kira Shaw
Andre M. Chagas
Letitia McMullan
Alexandra Webber
Kirsty McGowan
Sarah L. King
Catherine N. Hall
author_sort Silvia Anderle
collection DOAJ
description Abstract Reduced cerebral blood flow occurs early in the development of Alzheimer’s disease (AD), but the factors producing this reduction are unknown. Here, we ask whether genetic and lifestyle risk factors for AD—the ε4 allele of the Apolipoprotein (APOE) gene, and physical activity—can together produce this reduction in cerebral blood flow which leads eventually to AD. Using in vivo two-photon microscopy and haemodynamic measures, we record neurovascular function from the visual cortex of physically active or sedentary mice expressing APOE3 and APOE4 in place of murine APOE. Energy supply and demand are mismatched in APOE4 mice, with smaller increases in cerebral blood flow, blood volume and blood oxygenation occurring during neuronal activation as blood vessels frequently fail to dilate. Exercise dose-dependently overall improves neurovascular function, with an increased impact of exercise apparent after longer exposure times. Several haemodynamic measures show a larger beneficial effect of exercise in APOE4 vs. APOE3 mice. Thus, APOE4 genotype in conjunction with sedentary behaviour produces the worst neurovascular function. Promotion of physical activity may therefore be particularly important to improve cerebrovascular function and reduce dementia risk in APOE4 carriers.
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issn 2399-3642
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spelling doaj-art-914926835b534076ab40a2519287cbcb2025-02-02T12:37:29ZengNature PortfolioCommunications Biology2399-36422025-01-018111810.1038/s42003-025-07585-zAPOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake miceSilvia Anderle0Orla Bonnar1Joseph Henderson2Kira Shaw3Andre M. Chagas4Letitia McMullan5Alexandra Webber6Kirsty McGowan7Sarah L. King8Catherine N. Hall9School of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexSchool of Psychology and Sussex Neuroscience, University of SussexAbstract Reduced cerebral blood flow occurs early in the development of Alzheimer’s disease (AD), but the factors producing this reduction are unknown. Here, we ask whether genetic and lifestyle risk factors for AD—the ε4 allele of the Apolipoprotein (APOE) gene, and physical activity—can together produce this reduction in cerebral blood flow which leads eventually to AD. Using in vivo two-photon microscopy and haemodynamic measures, we record neurovascular function from the visual cortex of physically active or sedentary mice expressing APOE3 and APOE4 in place of murine APOE. Energy supply and demand are mismatched in APOE4 mice, with smaller increases in cerebral blood flow, blood volume and blood oxygenation occurring during neuronal activation as blood vessels frequently fail to dilate. Exercise dose-dependently overall improves neurovascular function, with an increased impact of exercise apparent after longer exposure times. Several haemodynamic measures show a larger beneficial effect of exercise in APOE4 vs. APOE3 mice. Thus, APOE4 genotype in conjunction with sedentary behaviour produces the worst neurovascular function. Promotion of physical activity may therefore be particularly important to improve cerebrovascular function and reduce dementia risk in APOE4 carriers.https://doi.org/10.1038/s42003-025-07585-z
spellingShingle Silvia Anderle
Orla Bonnar
Joseph Henderson
Kira Shaw
Andre M. Chagas
Letitia McMullan
Alexandra Webber
Kirsty McGowan
Sarah L. King
Catherine N. Hall
APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice
Communications Biology
title APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice
title_full APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice
title_fullStr APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice
title_full_unstemmed APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice
title_short APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice
title_sort apoe4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice
url https://doi.org/10.1038/s42003-025-07585-z
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