@article{9aba8c967d554ca5bcfa9719ef0f8e82,
title = "Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats",
abstract = "Dementia is a major social and economic problem for our aging population. One of the most common causes of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause. In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single-nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD.",
author = "Rajani, {Rikesh M.} and Sophie Quick and Ruigrok, {Silvie R.} and Delyth Graham and Harris, {Sarah E.} and Verhaaren, {Benjamin F.J.} and Myriam Fornage and Sudha Seshadri and Atanur, {Santosh S.} and Dominiczak, {Anna F.} and Colin Smith and Wardlaw, {Joanna M.} and Anna Williams",
note = "Funding Information: This work was supported by the UK Medical Research Council, Alzheimer's Research UK, Fondation Leducq (16 CVD 05), and the British Heart Foundation Centre for Research Excellence (RE/13/5/30177). S.E.H. is supported by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, funded by the MRC and Biotechnology and Biological Sciences Research Council (grant no. MR/K026992/1). Funding Information: The overall goal of this study was to determine the mechanism of pathology in cerebral SVD using early presymptomatic human tissue and a rat model of the disease. The use of human tissue for this study was approved by the Medical Research Council Edinburgh Brain and Tissue Bank. This bank has ethical approval to collect tissue for research after informed consent from the next of kin. All animal experiments were carried out in line with UK Home Office guidelines, under project licenses 60/4268 (D.G.), 70/9021 (D.G.), and 60/4524 (A.W.). Treatment groups were randomly assigned, data were analyzed by blinded observers, and biological replicate numbers were stated with each result along with the statistical test used. SHRSP and matched control strain, WKY, were housed at the University of Glasgow. Animals were fed standard chow and housed in line with UK Home Office guidelines. Breeding SHRSP pairs regularly had their blood pressure tested to ensure maintenance of the colony{\textquoteright}s phenotype. Male animals were exclusively used for both WKY controls and SHRSPs because SHRSP males display a more severe phenotype. Sprague-Dawley rats housed at the University of Edinburgh were used for wild-type OPCs and slice cultures. Publisher Copyright: Copyright {\textcopyright} 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",
year = "2018",
month = jul,
day = "4",
doi = "10.1126/scitranslmed.aam9507",
language = "English (US)",
volume = "10",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "448",
}