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Prenatal high-fat diet alters the cerebrovasculature and clearance of β-amyloid in adult offspring

Hawkes, Cheryl A.; Gentleman, Steve M.; Nicoll, James A. R. and Carare, Roxana O. (2015). Prenatal high-fat diet alters the cerebrovasculature and clearance of β-amyloid in adult offspring. Journal of Pathology, 235(4) pp. 619–631.

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Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides in the extracellular spaces of the brain as plaques and in the walls of blood vessels as cerebral amyloid angiopathy (CAA). Failure of perivascular drainage of Aβ along cerebrovascular basement membranes contributes to the development of CAA. Mid-life hypercholesterolaemia is a risk factor for the development of AD. Maternal obesity is associated with the development of obesity, hypertension and hypercholesterolaemia in adulthood, suggesting that the risk for AD and CAA may also be influenced by the early-life environment. In the present study, we tested the hypothesis that early-life exposure to a high-fat diet results in changes to the cerebrovasculature and failure of Aβ clearance from the brain. We also assessed whether vascular Aβ deposition is greater in the brains of aged humans with a history of hyperlipidaemia, compared to age-matched controls with normal lipidaemia. Using a mouse model of maternal obesity, we found that exposure to a high-fat diet during gestation and lactation induced changes in multiple components of the neurovascular unit, including a down-regulation in collagen IV, fibronectin and apolipoprotein E, an up-regulation in markers of astrocytes and perivascular macrophages and altered blood vessel morphology in the brains of adult mice. Sustained high-fat diet over the entire lifespan resulted in additional decreases in levels of pericytes and impaired perivascular clearance of Aβ from the brain. In humans, vascular Aβ load was significantly increased in the brains of aged individuals with a history of hypercholesterolaemia. These results support a critical role for early dietary influence on the brain vasculature across the lifespan, with consequences for the development of age-related cerebrovascular and neurodegenerative diseases.

Item Type: Journal Item
Copyright Holders: 2014 Pathological Society of Great Britain and Ireland
ISSN: 1096-9896
Keywords: maternal obesity; cerebral vasculature; brain; amyloid; Alzheimer's disease
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
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Item ID: 44078
Depositing User: Cheryl Hawkes
Date Deposited: 17 Sep 2015 08:42
Last Modified: 22 May 2019 13:34
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