The University of Southampton
University of Southampton Institutional Repository

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

Prenatal high-fat diet alters the cerebrovasculature and clearance of beta-amyloid in adult offspring
Prenatal high-fat diet alters the cerebrovasculature and clearance of beta-amyloid in adult offspring
Alzheimer's disease (AD) is characterized by the accumulation of ?-amyloid (A?) 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 A? 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 A? clearance from the brain. We also assessed whether vascular A? 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 A? from the brain. In humans, vascular A? 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.
619-631
Hawkes, Cheryl A.
a5bad078-e0fe-462c-989e-f0acd95892de
Gentleman, Steve M.
d28d75f7-05cf-4bca-8f3a-db15ce846466
Nicoll, James A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Hawkes, Cheryl A.
a5bad078-e0fe-462c-989e-f0acd95892de
Gentleman, Steve M.
d28d75f7-05cf-4bca-8f3a-db15ce846466
Nicoll, James A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa

Hawkes, Cheryl A., Gentleman, Steve M., Nicoll, James A.R. and Carare, Roxana-Octavia (2015) Prenatal high-fat diet alters the cerebrovasculature and clearance of beta-amyloid in adult offspring. The Journal of Pathology, 235 (4), 619-631. (doi:10.1002/path.4468). (PMID:25345857)

Record type: Article

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of ?-amyloid (A?) 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 A? 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 A? clearance from the brain. We also assessed whether vascular A? 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 A? from the brain. In humans, vascular A? 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.

Full text not available from this repository.

More information

Accepted/In Press date: 12 October 2014
e-pub ahead of print date: 7 January 2015
Published date: March 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 394800
URI: https://eprints.soton.ac.uk/id/eprint/394800
PURE UUID: 68c3a577-ba60-461d-82ec-caff1b09ccac
ORCID for James A.R. Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

Catalogue record

Date deposited: 24 May 2016 10:27
Last modified: 06 Jun 2018 12:49

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×