title: LDL-lipids from patients with hypercholesterolaemia and Alzheimer's disease are inflammatory to microvascular endothelial cells: mitigation by statin intervention.
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 F2α) 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 F2α (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.
authors.affiliation: Life and Health Sciences, Aston University, Birmingham, B4 7ET, West Midlands, U.K.
authors.forename: H K Irundika
authors.initials: HK
authors.lastname: Dias
authors.affiliation: Life and Health Sciences, Aston University, Birmingham, B4 7ET, West Midlands, U.K.
authors.forename: Caroline L R
authors.initials: CL
authors.lastname: Brown
authors.affiliation: Ageing Clinical Research, Department of Medicine II, University Hospital of Cologne, Cologne, D-50937, Germany.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Polidori
authors.affiliation: Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, U.K.
authors.forename: Gregory Y H
authors.initials: GY
authors.lastname: Lip
authors.affiliation: Life and Health Sciences, Aston University, Birmingham, B4 7ET, West Midlands, U.K. h.r.griffiths@aston.ac.uk.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Griffiths
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000175:diagnosis; D015415:Biomarkers / Q000097:blood; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004739:England; D005858:Germany; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D018836:Inflammation Mediators / Q000097:blood*; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D050050:Protein Carbonylation / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D019821:Simvastatin
keywords: Alzheimer's disease; blood–brain barrier; endothelium; lipids; statins