Universität zu Köln

Dias, H. K. Irundika, Brown, Caroline L. R., Polidori, M. Cristina, Lip, Gregory Y. H. and Griffiths, Helen R. (2015). LDL-lipids from patients with hypercholesterolaemia and Alzheimer's disease are inflammatory to microvascular endothelial cells: mitigation by statin intervention. Clin. Sci., 129 (12). S. 1195 - 1207. LONDON: PORTLAND PRESS LTD. ISSN 1470-8736

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Abstract

Elevated low-density lipoprotein (LDL) concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidized LDL (oxLDL) modification and nitration is observed during dementia and hypercholesterolaemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVECs) were maintained in transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naive, normo- and hyper-lipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40 mg of simvastatin intervention/day for 3 months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after 3 months. LDL isolated from statin-naive hyperlipidaemic, AD and AD-plus subjects was more oxidized (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2 alpha) compared with control subjects. Statin intervention decreased protein carbonyls (2.5 +/- 0.4 compared with 3.95 +/- 0.2 nmol/mg; P<0.001) and 8-isoprostane F2 alpha (30.4 +/- 4.0 pg/ml compared with 43.5 +/- 8.42 pg/ml; P<0.05). HMVEC treatment with LDL-lipids (LDL-L) from hyperlipidaemic, AD and AD-plus subjects impaired endothelial tight junction expression and decreased total glutathione levels (AD; 18.61 +/- 1.3, AD-plus; 16.5 +/- 0.7 nmol/mg of protein) compared with untreated cells (23.8 +/- 1.2 compared with nmol/mg of protein). Basolateral interleukin (IL)-6 secretion was increased by LDL-L from hyperlipidaemic (78.4 +/- 1.9 pg/ml), AD (63.2 +/- 5.9 pg/ml) and AD-plus (80.8 +/- 0.9 pg/ml) groups compared with healthy subject lipids (18.6 +/- 3.6 pg/ml). LDL-L isolated after statin intervention did not affect endothelial function. In summary, LDL-L from hypercholesterolaemic, AD and AD-plus patients are inflammatory to HMVECs. In vivo intervention with statins reduces the damaging effects of LDL-L on HMVECs.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dias, H. K. Irundika UNSPECIFIED UNSPECIFIED UNSPECIFIED Brown, Caroline L. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Polidori, M. Cristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Lip, Gregory Y. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Griffiths, Helen R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-385806
DOI:	10.1042/CS20150351
Journal or Publication Title:	Clin. Sci.
Volume:	129
Number:	12
Page Range:	S. 1195 - 1207
Date:	2015
Publisher:	PORTLAND PRESS LTD
Place of Publication:	LONDON
ISSN:	1470-8736
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BLOOD-BRAIN-BARRIER; OXIDATIVE STRESS; COGNITIVE IMPAIRMENT; VASCULAR DEMENTIA; CHOLESTEROL; MICE; NEURODEGENERATION; ATHEROSCLEROSIS; SENESCENCE; INCREASE Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38580