The pleiotropic vasoprotective functions of high density lipoproteins (HDL)

Abstract

The pleiotropic functions of circulating high density lipoprotein (HDL) on peripheral vascular health are well established. HDL plays a pivotal role in reverse cholesterol transport and is also known to suppress inflammation, endothelial activation and apoptosis in peripheral vessels. Although not expressed in the central nervous system, HDL has nevertheless emerged as a potential resilience factor for dementia in multiple epidemiological studies. Animal model data specifically support a role for HDL in attenuating the accumulation of β-amyloid within cerebral vessels concomitant with reduced neuroinflammation and improved cognitive performance. As the vascular contributions to dementia are increasingly appreciated, this review seeks to summarize recent literature focused on the vasoprotective properties of HDL that may extend to cerebral vessels, discuss potential roles of HDL in dementia relative to brain-derived lipoproteins, identify gaps in current knowledge, and highlight new opportunities for research and discovery.

Keywords

high density lipoprotein / vascular function / vascular disease / alzheimer disease / HDL-proteome / HDL-lipidome

References

[1] Rye KA. High density lipoprotein structure, function, and metabolism: a new Thematic Series[J]. J Lipid Res, 2013, 54(8): 2031–2033

[2] Murphy AJ. High Density Lipoprotein : Assembly, Structure, Cargo, and Functions[J]. ISRN Physiol, 2013; 2013(5): 1–20.

[3] Kontush A, Lhomme M. Lipidomics of plasma high-density lipoprotein: insights into anti-atherogenic function[J]. J Glycomics Lipidomics, 2015, 5: 3–6.

[4] Davidson. HDL Proteome Watch[J]. http://homepages.uc.edu/~davidswm/HDLproteome.html. 2015, accessed 1 July 2016.

[5] Shah AS, Tan L, Long JL, Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond[J]. J Lipid Res, 2013, 54(10): 2575–2585

[6] Lüscher TF, Landmesser U, von Eckardstein A, High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target[J]. Circ Res, 2014, 114(1): 171–182

[7] Riwanto M, Rohrer L, Roschitzki B, Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling[J]. Circulation, 2013, 127(8): 891–904

[8] Kannel WB, Dawber TR, Friedman GD, Risk factors in coronary heart disease: an evaluation of several serum lipids as predictors of coronary heart disease: the framingham study[J]. Ann Intern Med, 1964, 61: 888–899

[9] Gordon T, Castelli WP, Hjortland MC, High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study[J]. Am J Med, 1977, 62(5): 707–714

[10] Gordon DJ, Probstfield JL, Garrison RJ, High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies[J]. Circulation, 1989, 79(1): 8–15

[11] Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Data on plasma levels of apolipoprotein E, correlations with lipids and lipoproteins stratified by APOE genotype, and risk of ischemic heart disease[J]. Data Brief, 2016, 6: 923–932

[12] Swerdlow DI, Kuchenbaecker KB, Shah S, Selecting instruments for Mendelian randomization in the wake of genome-wide association studies[J]. Int J Epidemiol, 2016, 45(5): 1600–1616

[13] Holmes MV, Asselbergs FW, Palmer TM, , and the UCLEB consortium. Mendelian randomization of blood lipids for coronary heart disease[J]. Eur Heart J, 2015, 36(9): 539–550

[14] Voight BF, Peloso GM, Orho-Melander M, Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study[J]. Lancet, 2012, 380(9841): 572–580

[15] Weissglas-Volkov D, Pajukanta P. Genetic causes of high and low serum HDL-cholesterol[J]. J Lipid Res, 2010, 51(8): 2032–2057

[16] Sirtori CR, Calabresi L, Franceschini G, Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study[J]. Circulation, 2001, 103(15): 1949–1954

[17] Zanoni P, Khetarpal SA, Larach DB, , and the CHD Exome+ Consortium, and the CARDIoGRAM Exome Consortium, and the Global Lipids Genetics Consortium. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease[J]. Science, 2016, 351(6278): 1166–1171

[18] Gordon SM, Li H, Zhu X, A comparison of the mouse and human lipoproteome: suitability of the mouse model for studies of human lipoproteins[J]. J Proteome Res, 2015, 14(6): 2686–2695

[19] Getz GS, Reardon CA. Animal models of atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2012, 32(5): 1104–1115

[20] von Eckardstein A, Kardassis D. High density lipoproteins: From biological understanding to clinical exploitation[J]. In: Handbook of Experimental Pharmacology. 2015, pp. 593–615.

[21] Feig JE, Hewing B, Smith JD, High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies[J]. Circ Res, 2014, 114(1): 205–213

[22] Potočnjak I, Degoricija V, Trbušić M, Metrics of High-Density Lipoprotein Function and Hospital Mortality in Acute Heart Failure Patients[J]. PLoS One, 2016, 11(6): e0157507

[23] Monette JS, Hutchins PM, Ronsein GE, Patients With Coronary Endothelial Dysfunction Have Impaired Cholesterol Efflux Capacity and Reduced HDL Particle Concentration[J]. Circ Res, 2016, 119(1): 83–90

[24] Norimatsu K, Kuwano T, Miura S, Significance of the percentage of cholesterol efflux capacity and total cholesterol efflux capacity in patients with or without coronary artery disease[J]. Heart Vessels; [Epub 2016 Apr 22].

[25] Ishikawa T, Ayaori M, Uto-Kondo H, High-density lipoprotein cholesterol efflux capacity as a relevant predictor of atherosclerotic coronary disease[J]. Atherosclerosis, 2015, 242(1): 318–322

[26] Bounafaa A, Berrougui H, Ikhlef S, Alteration of HDL functionality and PON1 activities in acute coronary syndrome patients[J]. Clin Biochem, 2014, 47(18): 318–325

[27] Annema W, Dikkers A, de Boer JF, Impaired HDL cholesterol efflux in metabolic syndrome is unrelated to glucose tolerance status: the CODAM study[J]. Sci Rep, 2016, 6: 27367

[28] Vaisar T, Tang C, Babenko I, Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity[J]. J Lipid Res, 2015, 56(8): 1519–1530

[29] Agarwal R, Talwar P, Kushwaha SS, Effect of apolipoprotein E (APO E) polymorphism on leptin in Alzheimer’s disease[J]. Ann Indian Acad Neurol, 2015, 18(3): 320–326

[30] Rohatgi A. High-Density Lipoprotein Function Measurement in Human Studies: Focus on Cholesterol Efflux Capacity[J]. Prog Cardiovasc Dis, 2015, 58(1): 32–40

[31] Cameron SJ, Morrell CN, Bao C, A novel anti-inflammatory effect for high density lipoprotein[J]. PLoS One, 2015, 10(12): e0144372

[32] Fruhwürth S, Krieger S, Winter K, Inhibition of mTOR down-regulates scavenger receptor, class B, type i (SR-BI) expression, reduces endothelial cell migration and impairs nitric oxide production[J]. Biochim Biophys Acta- Mol Cell Biol Lipids 2014; 1841: 944–953.

[33] Pan B, Kong J, Jin J, A novel anti-inflammatory mechanism of high density lipoprotein through up-regulating annexin A1 in vascular endothelial cells[J]. Biochim Biophys Acta 2016; 1861: 501–512.

[34] Galvani S, Sanson M, Blaho VA, HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation[J]. Sci Signal, 2015, 8(389): ra79

[35] Kimura T, Tomura H, Mogi C, Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells[J]. J Biol Chem, 2006, 281(49): 37457–37467

[36] Terasaka N, Yu S, Yvan-Charvet L, ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet[J]. J Clin Invest, 2008, 118(11): 3701–3713

[37] Uittenbogaard A, Shaul PW, Yuhanna IS, High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae[J]. J Biol Chem, 2000, 275(15): 11278–11283

[38] Mackness MI, Arrol S, Abbott C, Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase[J]. Atherosclerosis, 1993, 104(1-2): 129–135

[39] Garcia-Heredia A, Marsillach J, Rull A, Paraoxonase-1 inhibits oxidized low-density lipoprotein-induced metabolic alterations and apoptosis in endothelial cells: A nondirected metabolomic study[J]. Mediators Inflamm 2013; 2013: 156053.

[40] Sattler K, Gräler M, Keul P, Defects of High-Density Lipoproteins in Coronary Artery Disease Caused by Low Sphingosine-1-Phosphate Content: Correction by Sphingosine-1-Phosphate-Loading[J]. J Am Coll Cardiol, 2015, 66(13): 1470–1485

[41] Oberbach A, Adams V, Schlichting N, Proteome profiles of HDL particles of patients with chronic heart failure are associated with immune response and also include bacteria proteins[J]. Clin Chim Acta, 2016, 453: 114–122

[42] Kaseda R, Jabs K, Hunley TE, Dysfunctional high-density lipoproteins in children with chronic kidney disease[J]. Metabolism, 2015, 64(2): 263–273

[43] Shroff R, Speer T, Colin S, HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype[J]. J Am Soc Nephrol, 2014, 25(11): 2658–2668

[44] O’Neill F, Riwanto M, Charakida M, Structural and functional changes in HDL with low grade and chronic inflammation[J]. Int J Cardiol, 2015, 188: 111–116

[45] Burillo E, Lindholt JS, Molina-Sánchez P, ApoA-I/HDL-C levels are inversely associated with abdominal aortic aneurysm progression[J]. Thromb Haemost, 2015, 113(6): 1335–1346

[46] Delbosc S, Diallo D, Dejouvencel T, Impaired high-density lipoprotein anti-oxidant capacity in human abdominal aortic aneurysm[J]. Cardiovasc Res, 2013, 100(2): 307–315

[47] Sang H, Yao S, Zhang L, Walk-run training improves the anti-inflammation properties of high-density lipoprotein in patients with metabolic syndrome[J]. J Clin Endocrinol Metab, 2015, 100(3): 870–879

[48] Rosenson RS. The High-Density Lipoprotein Puzzle: Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict[J]? Arterioscler Thromb Vasc Biol, 2016, 36(5): 777–782

[49] Kingwell BA, Chapman MJ, Kontush A, HDL-targeted therapies: progress, failures and future[J]. Nat Rev Drug Discov, 2014, 13(6): 445–464

[50] Heinecke JW. The not-so-simple HDL story: A new era for quantifying HDL and cardiovascular risk[J]? Nat Med, 2012, 18(9): 1346–1347

[51] Barter P, Gotto AM, LaRosa JC, , and the Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events[J]. N Engl J Med, 2007, 357(13): 1301–1310

[52] Ridker PM, Genest J, Boekholdt SM, , and the JUPITER Trial Study Group. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial[J]. Lancet, 2010, 376(9738): 333–339

[53] Duggal JK, Singh M, Attri N, Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease[J]. J Cardiovasc Pharmacol Ther, 2010, 15(2): 158–166

[54] Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis[J]. Atherosclerosis, 2010, 210(2): 353–361

[55] ]Sorrentino SA, Besler C, Rohrer L, Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy[J]. Circulation, 2010, 121(1): 110–122

[56] Landray MJ, Haynes R, Hopewell JC, , and the HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients[J]. N Engl J Med, 2014, 371(3): 203–212

[57] Wheeler AP, Bernard GR, Thompson BT, , and the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury[J]. N Engl J Med, 2006, 354(21): 2213–2224

[58] Keene D, Price C, Shun-Shin MJ, Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients[J]. BMJ, 2014, 349: g4379

[59] Musunuru K, Orho-Melander M, Caulfield MP, Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk[J]. Arterioscler Thromb Vasc Biol, 2009, 29(11): 1975–1980

[60] Phillips CM, Perry IJ. Lipoprotein particle subclass profiles among metabolically healthy and unhealthy obese and non-obese adults: does size matter[J]? Atherosclerosis, 2015, 242(2): 399–406

[61] Xu RX, Zhang Y, Ye P, Analysis of Lipoprotein Subfractions in Chinese Han Patients with Stable Coronary Artery Disease[J]. Heart Lung Circ, 2015, 24(12): 1203–1210

[62] Li JJ, Zhang Y, Li S, Large HDL Subfraction But Not HDL-C Is Closely Linked With Risk Factors, Coronary Severity and Outcomes in a Cohort of Nontreated Patients With Stable Coronary Artery Disease: A Prospective Observational Study[J]. Medicine (Baltimore), 2016, 95(4): e2600

[63] Bostan M, Uydu HA, Yildirmiş S, Pleiotropic effects of HDL subfractions and HDL-associated enzymes on protection against coronary artery disease[J]. Acta Cardiol, 2015, 70(3): 333–340

[64] McGarrah RW, Craig DM, Haynes C, High-density lipoprotein subclass measurements improve mortality risk prediction, discrimination and reclassification in a cardiac catheterization cohort[J]. Atherosclerosis, 2016, 246: 229–235

[65] Tian L, Chen Y, Li C, Statin treatment improves plasma lipid levels but not HDL subclass distribution in patients undergoing percutaneous coronary intervention[J]. Lipids, 2013, 48(2): 127–137

[66] Berthold HK, Rizzo M, Spenrath N, Effects of lipid-lowering drugs on high-density lipoprotein subclasses in healthy men-a randomized trial[J]. PLoS One, 2014, 9(3): e91565

[67] Asztalos BF, Le Maulf F, Dallal GE, Comparison of the effects of high doses of rosuvastatin versus atorvastatin on the subpopulations of high-density lipoproteins[J]. Am J Cardiol, 2007, 99(5): 681–685

[68] Harangi M, Mirdamadi HZ, Seres I, Atorvastatin effect on the distribution of high-density lipoprotein subfractions and human paraoxonase activity[J]. Transl Res, 2009, 153(4): 190–198

[69] Ronsein GE, Hutchins PM, Isquith D, Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects[J]. Arterioscler Thromb Vasc Biol, 2016, 36(2): 404–411

[70] Mendivil CO, Furtado J, Morton AM, Novel Pathways of Apolipoprotein A-I Metabolism in High-Density Lipoprotein of Different Sizes in Humans[J]. Arterioscler Thromb Vasc Biol, 2016, 36(1): 156–165

[71] Niculescu LS, Simionescu N, Sanda GM, MiR-486 and miR-92a identified in circulating HDL discriminate between stable and vulnerable coronary artery disease patients[J]. PLoS One, 2015, 10(10): e0140958

[72] Trieb M, Horvath A, Birner-Gruenberger R, Liver disease alters high-density lipoprotein composition, metabolism and function[J]. Biochim Biophys Acta 2016; 1861: 630–638.

[73] [Marsillach J, Aragonès G, Mackness B, Decreased paraoxonase-1 activity is associated with alterations of high-density lipoprotein particles in chronic liver impairment[J]. Lipids Health Dis, 2010, 9: 46

[74] Gomaraschi M, Ossoli A, Favari E, Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome[J]. Cardiovasc Res, 2013, 100(1): 36–43

[75] Shao B, de Boer I, Tang C, A Cluster of Proteins Implicated in Kidney Disease Is Increased in High-Density Lipoprotein Isolated from Hemodialysis Subjects[J]. J Proteome Res, 2015, 14(7): 2792–2806

[76] Sun JT, Yang K, Lu L, Increased carbamylation level of HDL in end-stage renal disease: carbamylated-HDL attenuated endothelial cell function[J]. Am J Physiol Renal Physiol, 2016, 310(6): F511–F517

[77] Gómez Rosso L, Lhomme M, Meroño T, Altered lipidome and antioxidative activity of small, dense HDL in normolipidemic rheumatoid arthritis: relevance of inflammation[J]. Atherosclerosis, 2014, 237(2): 652–660

[78] Holzer M, Trieb M, Konya V, Aging affects high-density lipoprotein composition and function[J]. Biochim Biophys Acta- Mol Cell Biol Lipids 2013; 1831: 1442–1448.

[79] Jaouad L, de Guise C, Berrougui H, Age-related decrease in high-density lipoproteins antioxidant activity is due to an alteration in the PON1's free sulfhydryl groups[J]. Atherosclerosis, 2006, 185(1): 191–200

[80] Pedret A, Catalán Ú, Fernández-Castillejo S, Impact of virgin olive oil and phenol-enriched virgin olive oils on the HDL proteome in hypercholesterolemic subjects: A double blind, randomized, controlled, cross-over clinical trial (VOHF study)[J]. PLoS One, 2015, 10(6): e0129160

[81] Holzer M, Birner-Gruenberger R, Stojakovic T, Uremia alters HDL composition and function[J]. J Am Soc Nephrol, 2011, 22(9): 1631–1641

[82] Ahnström J, Gottsäter A, Lindblad B, Plasma concentrations of apolipoproteins A-I, B and M in patients with abdominal aortic aneurysms[J]. Clin Biochem, 2010, 43(4-5): 407–410

[83] Gamberi T, Puglia M, Guidi F, A proteomic approach to identify plasma proteins in patients with abdominal aortic aneurysm[J]. Mol Biosyst, 2011, 7(10): 2855–2862

[84] Krishnan S, Huang J, Lee H, Combined High-Density Lipoprotein Proteomic and Glycomic Profiles in Patients at Risk for Coronary Artery Disease[J]. J Proteome Res, 2015, 14(12): 5109–5118

[85] Sánchez-Quesada JL, Vinagre I, De Juan-Franco E, Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes[J]. Cardiovasc Diabetol, 2013, 12: 112

[86] Green PS, Vaisar T, Subramaniam P, Combined Statin and Niacin Therapy Remodels the HDL Proteome.[J] Circulation, 2008, 118(12): 1259–1267.

[87] Yetukuri L, Huopaniemi I, Koivuniemi A, High density lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy[J]. PLoS One, 2011, 6(8): e23589

[88] Gordon SM, McKenzie B, Kemeh G, Rosuvastatin Alters the Proteome of High Density Lipoproteins: Generation of alpha-1-antitrypsin Enriched Particles with Anti-inflammatory Properties[J]. Mol Cell Proteomics, 2015, 14(12): 3247–3257

[89] Kontush A, Lhomme M, Chapman MJ. Unraveling the complexities of the HDL lipidome[J]. J Lipid Res, 2013, 54(11): 2950–2963

[90] Argraves KM, Sethi AA, Gazzolo PJ, S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease[J]. Lipids Health Dis, 2011, 10: 70

[91] Tong X, Lv P, Mathew AV, The compensatory enrichment of sphingosine-1- phosphate harbored on glycated high-density lipoprotein restores endothelial protective function in type 2 diabetes mellitus[J]. Cardiovasc Diabetol, 2014, 13: 82

[92] Vickers KC, Remaley AT. Functional Diversity of HDL Cargo[J]. J Lipid Res 2013; jlr.R035964v2.

[93] Desgagné V, Guay SP, Guérin R, Variations in HDL-carried miR-223 and miR-135a concentrations after consumption of dietary trans fat are associated with changes in blood lipid and inflammatory markers in healthy men- an exploratory study[J]. Epigenetics, 2016, 11(6): 438–448

[94] Tabet F, Cuesta Torres LF, Ong KL, High-Density Lipoprotein-Associated miR-223 Is Altered after Diet-Induced Weight Loss in Overweight and Obese Males[J]. PLoS One, 2016, 11(3): e0151061

[95] Vickers KC, Palmisano BT, Shoucri BM, MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins[J]. Nat Cell Biol, 2011, 13(4): 423–433

[96] Tabet F, Vickers KC, Cuesta Torres LF, HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells[J]. Nat Commun, 2014, 5: 3292

[97] Hyötyläinen T, Mattila I, Wiedmer SK, Metabolomic analysis of polar metabolites in lipoprotein fractions identifies lipoprotein-specific metabolic profiles and their association with insulin resistance[J]. Mol Biosyst, 2012, 8(10): 2559–2565

[98] Speer T, Rohrer L, Blyszczuk P, Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2[J]. Immunity, 2013, 38(4): 754–768

[99] Chadwick AC, Holme RL, Chen Y, Acrolein impairs the cholesterol transport functions of high density lipoproteins[J]. PLoS One, 2015, 10(4): e0123138

[100] Fonslow BR, Stein BD, Webb KJ, Digestion and depletion of abundant proteins improves proteomic coverage[J]. Nat Methods, 2013, 10(1): 54–56

[101] Williams LR, Leggett RW. Reference values for resting blood flow to organs of man[J]. Clin Phys Physiol Meas, 1989, 10(3): 187–217

[102] Attems J, Jellinger KA. The overlap between vascular disease and Alzheimer’s disease--lessons from pathology[J]. BMC Med, 2014, 12: 206

[103] Iadecola C. The pathobiology of vascular dementia[J]. Neuron, 2013, 80(4): 844–866

[104] Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis[J]. Lancet Neurol, 2009, 8(11): 1006–1018

[105] Consortium M.METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration: An initiative of the Joint Programme for Neurodegenerative Disease Research[J]. Alzheimer’s Dement 2016; pii: S1552: 30064–4.

[106] World Health Organization[J]. Fact Sheet: Dementiahttp://www.who.int/mediacentre/factsheets/fs362/en/ (accessed 1 July 2016).

[107] De Strooper B, Karran E. The Cellular Phase of Alzheimer’s Disease[J]. Cell, 2016, 164(4): 603–615

[108] Bird TD. Early-Onset Familial Alzheimer Disease[J]. In: Pagon R, Adam M, Ardinger H, et al. (eds) GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle, 2012.

[109] Mathis CA, Kuller LH, Klunk WE, In vivo assessment of amyloid-β deposition in nondemented very elderly subjects[J]. Ann Neurol, 2013, 73(6): 751–761

[110] Meng XF, Yu JT, Wang HF, Midlife vascular risk factors and the risk of Alzheimer’s disease: a systematic review and meta-analysis[J]. J Alzheimers Dis, 2014, 42(4): 1295–1310

[111] Toledo JB, Arnold SE, Raible K, Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre[J]. Brain, 2013, 136(Pt 9): 2697–2706

[112] Kalaria RN. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease[J]. Acta Neuropathol, 2016, 131(5): 659–685

[113] Arvanitakis Z, Capuano AW, Leurgans SE, Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol, 2016, 15(9): 934–943

[114] Lee S, Viqar F, Zimmerman ME, , and the Dominantly Inherited Alzheimer Network. White matter hyperintensities are a core feature of Alzheimer’s disease: Evidence from the dominantly inherited Alzheimer network[J]. Ann Neurol, 2016, 79(6): 929–939

[115] Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci, 2011, 12(12): 723–738

[116] Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum[J]. J Neurol Neurosurg Psychiatry, 2012, 83(2): 124–137

[117] Yamada M. Cerebral amyloid angiopathy: emerging concepts[J]. J Stroke, 2015, 17(1): 17–30

[118] Yates PA, Villemagne VL, Ellis KA, Cerebral microbleeds: a review of clinical, genetic, and neuroimaging associations[J]. Front Neurol, 2014, 4: 205

[119] Kövari E, Charidimou A, Herrmann FR, No neuropathological evidence for a direct topographical relation between microbleeds and cerebral amyloid angiopathy[J]. Acta Neuropathol Commun, 2015, 3: 49

[120] Martinez-Ramirez S, Greenberg SM, Viswanathan A. Cerebral microbleeds: overview and implications in cognitive impairment[J]. Alzheimers Res Ther, 2014, 6(3): 33

[121] Akoudad S, Wolters FJ, Viswanathan A, Association of Cerebral Microbleeds With Cognitive Decline and Dementia[J]. JAMA Neurol, 2016, 73(8): 934–943

[122] van der Vlies AE, Goos JDC, Barkhof F, Microbleeds do not affect rate of cognitive decline in Alzheimer disease[J]. Neurology, 2012, 79(8): 763–769

[123] Wang N, Allali G, Kesavadas C, Cerebral Small Vessel Disease and Motoric Cognitive Risk Syndrome: Results from the Kerala-Einstein Study[J]. J Alzheimers Dis, 2016, 50(3): 699–707

[124] O’Brien JT, Thomas A. Vascular dementia[J]. Lancet, 2015, 386(10004): 1698–1706

[125] Mathias JL, Burke J. Cognitive functioning in Alzheimer’s and vascular dementia: a meta-analysis[J]. Neuropsychology, 2009, 23(4): 411–423

[126] Chui HC, Zheng L, Reed BR, Vascular risk factors and Alzheimer’s disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review[J]. Alzheimers Res Ther, 2012, 4(1): 1

[127] Jellinger KA. Pathology and pathogenesis of vascular cognitive impairment-a critical update[J]. Front Aging Neurosci, 2013, 5: 17

[128] Jellinger KA, Attems J. Prevalence of dementia disorders in the oldest-old: an autopsy study[J]. Acta Neuropathol, 2010, 119(4): 421–433

[129] Zhai Y, Yamashita T, Nakano Y, Chronic Cerebral Hypoperfusion Accelerates Alzheimer’s Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model[J]. J Alzheimers Dis, 2016, 53(3): 893–905

[130] Ly JV, Rowe CC, Villemagne VL, Subacute ischemic stroke is associated with focal 11C PiB positron emission tomography retention but not with global neocortical Aβ deposition[J]. Stroke, 2012, 43(5): 1341–1346

[131] Sahathevan R, Linden T, Villemagne VL, Positron emission tomographic imaging in stroke: Cross-sectional and follow-up assessment of amyloid in ischemic stroke[J]. Stroke, 2016, 47(1): 113–119

[132] Kerridge C, Kozlova DI, Nalivaeva NN, Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism[J]. Front Neurosci, 2015, 9: 426

[133] Dietschy JM. Central nervous system: cholesterol turnover, brain development and neurodegeneration[J]. Biol Chem, 2009, 390(4): 287–293

[134] Foley P.Lipids in Alzheimer’s disease: A century-old story[J]. Biochimica et Biophysica Acta- Molecular and Cell Biology of Lipids 2010; 1801: 750–753.

[135] Jones L, Harold D, Williams J. Genetic evidence for the involvement of lipid metabolism in Alzheimer’s disease[J]. Biochim Biophys Acta 2010; 1801: 754–761.

[136] Corder EH, Saunders AM, Strittmatter WJ, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families[J]. Science, 1993, 261(5123): 921–923

[137] Farrer LA, Cupples LA, Haines JL, , and the APOE and Alzheimer Disease Meta Analysis Consortium. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease[J]. A meta-analysis. JAMA, 1997, 278(16): 1349–1356

[138] Liu CC, Kanekiyo T, Xu H, Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy[J]. Nat Rev Neurol, 2013, 9(2): 106–118

[139] Shinohara M, Kanekiyo T, Yang L, APOE2 eases cognitive decline during aging: clinical and preclinical evaluations[J]. Ann Neurol; [Epub 2016 Mar 2].

[140] Rebeck GW, Reiter JS, Strickland DK, Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions[J]. Neuron, 1993, 11(4): 575–580

[141] Kok E, Haikonen S, Luoto T, Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age[J]. Ann Neurol, 2009, 65(6): 650–657

[142] Hultman K, Strickland S, Norris EH. The APOE ϵ4/ϵ4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer’s disease patients[J]. J Cereb Blood Flow Metab, 2013, 33(8): 1251–1258

[143] Polvikoski T, Sulkava R, Haltia M, Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein[J]. N Engl J Med, 1995, 333(19): 1242–1247

[144] Schmechel DE, Saunders AM, Strittmatter WJ, Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease[J]. Proc Natl Acad Sci U S A, 1993, 90(20): 9649–9653

[145] Tiraboschi P, Hansen LA, Masliah E, Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease[J]. Neurology, 2004, 62(11): 1977–1983

[146] Strittmatter WJ, Saunders AM, Schmechel D, Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease[J]. Proc Natl Acad Sci U S A, 1993, 90(5): 1977–1981

[147] Bennet AM, Di Angelantonio E, Ye Z, Association of apolipoprotein E genotypes with lipid levels and coronary risk[J]. JAMA, 2007, 298(11): 1300–1311

[148] Castellano JM, Kim J, Stewart FR, Human apoE isoforms differentially regulate brain amyloid-β peptide clearance[J]. Sci Transl Med, 2011, 3(89): 89ra57

[149] Tai LM, Thomas R, Marottoli FM, The role of APOE in cerebrovascular dysfunction[J]. Acta Neuropathol, 2016, 131(5): 709–723

[150] Ulrich V, Konaniah ES, Herz J, Genetic variants of ApoE and ApoER2 differentially modulate endothelial function[J]. Proc Natl Acad Sci U S A, 2014, 111(37): 13493–13498

[151] Bell RD, Winkler EA, Singh I, Apolipoprotein E controls cerebrovascular integrity via cyclophilin A[J]. Nature, 2012, 485(7399): 512–516

[152] Bangen KJ, Beiser A, Delano-Wood L, APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline[J]. J Stroke Cerebrovasc Dis, 2013, 22(8): 1361–1369

[153] Chai YL, Yeo HK, Wang J, Apolipoprotein ϵ4 is Associated with Dementia and Cognitive Impairment Predominantly Due to Alzheimer’s Disease and Not with Vascular Cognitive Impairment: A Singapore-Based Cohort[J]. J Alzheimers Dis, 2016, 51(4): 1111–1118

[154] Roheim PS, Carey M, Forte T, Apolipoproteins in human cerebrospinal fluid[J]. Proc Natl Acad Sci U S A, 1979, 76(9): 4646–4649

[155] Harold D, Abraham R, Hollingworth P, Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease[J]. Nat Genet, 2009, 41(10): 1088–1093

[156] Lambert JC, Heath S, Even G, , and the European Alzheimer’s Disease Initiative Investigators. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease[J]. Nat Genet, 2009, 41(10): 1094–1099

[157] Lidström AM, Bogdanovic N, Hesse C, Clusterin (apolipoprotein J) protein levels are increased in hippocampus and in frontal cortex in Alzheimer’s disease[J]. Exp Neurol, 1998, 154(2): 511–521

[158] Del Valle E, Navarro A, Martínez-Pinilla E, Apo J and Apo D: Complementary or Antagonistic Roles in Alzheimer’s Disease[J]? J Alzheimers Dis, 2016, 53(2): 639–650

[159] Manousopoulou A, Gatherer M, Smith C, Systems proteomic analysis reveals that Clusterin and Tissue Inhibitor of Metalloproteinases 3 increase in leptomeningeal arteries affected by cerebral amyloid angiopathy[J]. Neuropathol Appl Neurobiol; [Epub 2016 Oct 5].

[160] Bell RD, Sagare AP, Friedman AE, Transport pathways for clearance of human Alzheimer’s amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system[J]. J Cereb Blood Flow Metab, 2007, 27(5): 909–918

[161] Miners JS, Clarke P, Love S. Clusterin levels are increased in Alzheimer’s disease and influence the regional distribution of A[J]. Brain Pathol; [Epub 2016 Jun 1].

[162] Merino-Zamorano C, Fernández-de Retana S, Montañola A, Modulation of Amyloid-β1-40 Transport by ApoA1 and ApoJ Across an in vitro Model of the Blood-Brain Barrier[J]. J Alzheimers Dis, 2016, 53(2): 677–691

[163] Yeh FL, Wang Y, Tom I, TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia[J]. Neuron, 2016, 91(2): 328–340

[164] Beeg M, Stravalaci M, Romeo M, Clusterin binds to A??1–42 Oligomers with high affinity and interferes with peptide aggregation by inhibiting primary and secondary nucleation[J]. J Biol Chem, 2016, 291(13): 6958–6966

[165] Kang SS, Kurti A, Wojtas A, Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes[J]. Hum Mol Genet, 2016, 25(16): 3467–3475

[166] Desikan RS, Thompson WK, Holland D, , and the Alzheimer’s Disease Neuroimaging Initiative Group. The role of clusterin in amyloid-β-associated neurodegeneration[J]. JAMA Neurol, 2014, 71(2): 180–187

[167] Bates KA, Sohrabi HR, Rainey-Smith SR, Serum high-density lipoprotein is associated with better cognitive function in a cross-sectional study of aging women[J]. Int J Neurosci; [Epub 2016 May 15].

[168] Crichton GE, Elias MF, Davey A, Higher HDL cholesterol is associated with better cognitive function: the Maine-Syracuse study[J]. J Int Neuropsychol Soc, 2014, 20(10): 961–970

[169] Reed B, Villeneuve S, Mack W, Associations between serum cholesterol levels and cerebral amyloidosis[J]. JAMA Neurol, 2014, 71(2): 195–200

[170] Taniguchi Y, Shinkai S, Nishi M, Nutritional biomarkers and subsequent cognitive decline among community-dwelling older Japanese: a prospective study[J]. J Gerontol A Biol Sci Med Sci, 2014, 69(10): 1276–1283

[171] Dias IHK, Polidori MC, Li L, Plasma levels of HDL and carotenoids are lower in dementia patients with vascular comorbidities[J]. J Alzheimers Dis, 2014, 40(2): 399–408

[172] Shih YH, Tsai KJ, Lee CW, Apolipoprotein C-III is an amyloid-β-binding protein and an early marker for Alzheimer’s disease[J]. J Alzheimers Dis, 2014, 41(3): 855–865

[173] Choi HJ, Seo EH, Yi D, Amyloid-Independent Amnestic Mild Cognitive Impairment and Serum Apolipoprotein A1 Levels[J]. Am J Geriatr Psychiatry, 2016, 24(2): 144–153

[174] Hye A, Riddoch-Contreras J, Baird AL, Plasma proteins predict conversion to dementia from prodromal disease[J]. Alzheimers Dement, 2014, 10(6): 799–807.e2

[175] Yang Y, Keene CD, Peskind ER, Cerebrospinal Fluid Particles in Alzheimer Disease and Parkinson Disease[J]. J Neuropathol Exp Neurol, 2015, 74(7): 672–687

[176] Lin Q, Cao Y, Gao J. Decreased expression of the APOA1-APOC3-APOA4 gene cluster is associated with risk of Alzheimer’s disease[J]. Drug Des Devel Ther, 2015, 9: 5421–5431

[177] Batty GD, Russ TC, Starr JM, Modifiable cardiovascular disease risk factors as predictors of dementia death: pooling of ten general population-based cohort studies[J]. J Negat Results Biomed, 2014, 13: 8

[178] Østergaard SD, Mukherjee S, Sharp SJ, , and the Alzheimer’s Disease Genetics Consortium, and the GERAD1 Consortium, and the EPIC-InterAct Consortium. Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study[J]. PLoS Med, 2015, 12(6): e1001841, discussion e1001841

[179] Proitsi P, Lupton MK, Velayudhan L, , and the Alzheimer’s Disease Neuroimaging Initiative, and the GERAD1 Consortium. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis[J]. PLoS Med, 2014, 11(9): e1001713

[180] Vollbach H, Heun R, Morris CM, APOA1 polymorphism influences risk for early-onset nonfamiliar AD[J]. Ann Neurol, 2005, 58(3): 436–441

[181] Song F, Poljak A, Crawford J, Plasma apolipoprotein levels are associated with cognitive status and decline in a community cohort of older individuals[J]. PLoS One, 2012, 7(6): e34078

[182] Shibata N, Nagata T, Shinagawa S, Genetic association between APOA1 and APOD polymorphisms and Alzheimer’s disease in a Japanese population[J]. J Neural Transm (Vienna), 2013, 120(11): 1599–1603

[183] Lazarus J, Mather KA, Armstrong NJ, DNA methylation in the apolipoprotein-A1 gene is associated with episodic memory performance in healthy older individuals[J]. J Alzheimers Dis, 2015, 44(1): 175–182

[184] Cervellati C, Trentini A, Romani A, Serum paraoxonase and arylesterase activities of paraoxonase-1 (PON-1), mild cognitive impairment, and 2-year conversion to dementia: A pilot study[J]. J Neurochem, 2015, 135(2): 395–401

[185] Castellazzi M, Trentini A, Romani A, Decreased Arylesterase activity of Paraoxonase-1 (PON-1) might be a common denominator of neuroinflammatory and neurodegenerative diseases[J]. Int J Biochem Cell Biol 2016; S1357–2725: 30148–0.

[186] Fellows K, Uher T, Browne RW, Protective associations of HDL with blood-brain barrier injury in multiple sclerosis patients[J]. J Lipid Res, 2015, 56(10): 2010–2018

[187] Swanson CR, Berlyand Y, Xie SX, Plasma apolipoprotein A1 associates with age at onset and motor severity in early Parkinson’s disease patients[J]. Mov Disord, 2015, 30(12): 1648–1656

[188] Zhang X, Yin X, Yu H, Quantitative proteomic analysis of serum proteins in patients with Parkinson’s disease using an isobaric tag for relative and absolute quantification labeling, two-dimensional liquid chromatography, and tandem mass spectrometry[J]. Analyst, 2012, 137(2): 490–495

[189] Qiang JK, Wong YC, Siderowf A, Plasma apolipoprotein A1 as a biomarker for Parkinson disease[J]. Ann Neurol, 2013, 74(1): 119–127

[190] Lefterov I, Fitz NF, Cronican AA, Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice[J]. J Biol Chem, 2010, 285(47): 36945–36957

[191] Lewis TL, Cao D, Lu H, Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease[J]. J Biol Chem, 2010, 285(47): 36958–36968

[192] Robert J, Stukas S, Button E, Reconstituted high-density lipoproteins acutely reduce soluble brain A  levels in symptomatic APP / PS1 mice[J]. Biochim Biophys Acta 2016; 1862: 1027–36.

[193] Handattu SP, Garber DW, Monroe CE, Oral apolipoprotein A-I mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer’s disease[J]. Neurobiol Dis, 2009, 34(3): 525–534

[194] ]Koch S, Donarski N, Goetze K, Characterization of four lipoprotein classes in human cerebrospinal fluid[J]. J Lipid Res, 2001, 42(7): 1143–1151

[195] Stukas S, Robert J, Lee M, Intravenously injected human apolipoprotein A-I rapidly enters the central nervous system via the choroid plexus[J]. J Am Heart Assoc, 2014, 3(6): e001156

[196] Lapergue B, Dang BQ, Desilles JP, High-density lipoprotein-based therapy reduces the hemorrhagic complications associated with tissue plasminogen activator treatment in experimental stroke[J]. Stroke, 2013, 44(3): 699–707

[197] Lapergue B, Moreno JA, Dang BQ, Protective effect of high-density lipoprotein-based therapy in a model of embolic stroke[J]. Stroke, 2010, 41(7): 1536–1542

[198] Bao Dang Q, Lapergue B, Tran-Dinh A, High-density lipoproteins limit neutrophil-induced damage to the blood-brain barrier in vitro[J]. J Cereb Blood Flow Metab, 2013, 33(4): 575–582

[199] McGuinness B, Craig D, Bullock R, Statins for the prevention of dementia[J]. Cochrane Database Syst Rev, 2016, (1): CD003160

[200] Power MC, Weuve J, Sharrett AR, Statins, cognition, and dementia—systematic review and methodological commentary[J]. Nat Rev Neurol, 2015, 11(4): 220–229

[201] Lin FC, Chuang YS, Hsieh HM, Early Statin Use and the Progression of Alzheimer Disease: A Total Population-Based Case-Control Study[J]. Medicine (Baltimore), 2015, 94(47): e2143

[202] Chen PY, Liu SK, Chen CL, Long-term statin use and dementia risk in Taiwan[J]. J Geriatr Psychiatry Neurol, 2014, 27(3): 165–171

[203] Ancelin ML, Carrière I, Barberger-Gateau P, Lipid lowering agents, cognitive decline, and dementia: the three-city study[J]. J Alzheimers Dis, 2012, 30(3): 629–637

[204] Williamson JD, Launer LJ, Bryan RN, , and the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Investigators. Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels: a randomized clinical trial[J]. JAMA Intern Med, 2014, 174(3): 324–333

[205] Swiger KJ, Martin SS. PCSK9 inhibitors and neurocognitive adverse events: exploring the FDA directive and a proposal for N-of-1 trials[J]. Drug Saf, 2015, 38(6): 519–526

[206] Wang H, Blumberg JB, Chen CY, Dietary modulators of statin efficacy in cardiovascular disease and cognition[J]. Mol Aspects Med, 2014, 38: 1–53

[207] Hong C, Tontonoz P. Liver X receptors in lipid metabolism: opportunities for drug discovery[J]. Nat Rev Drug Discov, 2014, 13(6): 433–444

[208] Hirsch-Reinshagen V, Maia LF, Burgess BL, The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease[J]. J Biol Chem, 2005, 280(52): 43243–43256

[209] Koldamova R, Staufenbiel M, Lefterov I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice[J]. J Biol Chem, 2005, 280(52): 43224–43235

[210] Wahrle SE, Jiang H, Parsadanian M, Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease[J]. J Clin Invest, 2008, 118(2): 671–682

[211] Wahrle SE, Jiang H, Parsadanian M, ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE[J]. J Biol Chem, 2004, 279(39): 40987–40993

[212] Nordestgaard LT, Tybjærg-Hansen A, Nordestgaard BG, Loss-of-function mutation in ABCA1 and risk of Alzheimer’s disease and cerebrovascular disease[J]. Alzheimers Dement, 2015, 11(12): 1430–1438

[213] Cui X, Chopp M, Zacharek A, The neurorestorative benefit of GW3965 treatment of stroke in mice[J]. Stroke, 2013, 44(1): 153–161

[214] Fitz NF, Cronican A, Pham T, Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice[J]. J Neurosci, 2010, 30(20): 6862–6872

[215] Jiang Q, Lee CYD, Mandrekar S, ApoE promotes the proteolytic degradation of Abeta[J]. Neuron, 2008, 58(5): 681–693

[216] Koldamova RP, Lefterov IM, Staufenbiel M, The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease[J]. J Biol Chem, 2005, 280(6): 4079–4088

[217] LaClair KD, Manaye KF, Lee DL, Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice[J]. Mol Neurodegener, 2013, 8: 18

[218] Skerrett R, Pellegrino MP, Casali BT, Combined liver X receptor/peroxisome proliferator-activated receptor g agonist treatment reduces amyloid β levels and improves behavior in amyloid precursor protein/presenilin 1 mice[J]. J Biol Chem, 2015, 290(35): 21591–21602

[219] Sun Y, Fan J, Zhu Z, Small molecule TBTC as a new selective retinoid X receptor α agonist improves behavioral deficit in Alzheimer’s disease model mice[J]. Eur J Pharmacol, 2015, 762: 202–213

[220] Vanmierlo T, Rutten K, Dederen J, Liver X receptor activation restores memory in aged AD mice without reducing amyloid[J]. Neurobiol Aging, 2011, 32(7): 1262–1272

[221] Certo M, Endo Y, Ohta K, Activation of RXR/PPARg underlies neuroprotection by bexarotene in ischemic stroke[J]. Pharmacol Res, 2015, 102: 298–307

[222] Kim E, Woo MS, Qin L, Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke[J]. J Neurosci, 2015, 35(45): 15113–15126

[223] ElAli A, Hermann DM. Liver X receptor activation enhances blood-brain barrier integrity in the ischemic brain and increases the abundance of ATP-binding cassette transporters ABCB1 and ABCC1 on brain capillary cells[J]. Brain Pathol, 2012, 22(2): 175–187

[224] Sironi L, Mitro N, Cimino M, Treatment with LXR agonists after focal cerebral ischemia prevents brain damage[J]. FEBS Lett, 2008, 582(23-24): 3396–3400

[225] Morales JR, Ballesteros I, Deniz JM, Activation of liver X receptors promotes neuroprotection and reduces brain inflammation in experimental stroke[J]. Circulation, 2008, 118(14): 1450–1459

[226] Sandoval-Hernández AG, Restrepo A, Cardona-Gómez GP, LXR activation protects hippocampal microvasculature in very old triple transgenic mouse model of Alzheimer’s disease[J]. Neurosci Lett, 2016, 621: 15–21

[227] Donkin JJ, Stukas S, Hirsch-Reinshagen V, ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice[J]. J Biol Chem, 2010, 285(44): 34144–34154

[228] Stukas S, May S, Wilkinson A, The LXR agonist GW3965 increases apoA-I protein levels in the central nervous system independent of ABCA1. Biochim Biophys Acta- Mol Cell Biol Lipids 2012; 1821: 536–546.

[229] Cramer PE, Cirrito JR, Wesson DW, ApoE-Directed Therapeutics Rapidly Clear -Amyloid and Reverse Deficits in AD Mouse Models[J]. Science (80-) 2012; 335: 1503–1506.

[230] O’Hare E, Jeggo R, Kim EM, Lack of support for bexarotene as a treatment for Alzheimer’s disease[J]. Neuropharmacology, 2016, 100: 124–130

[231] Bomben V, Holth J, Reed J, Bexarotene reduces network excitability in models of Alzheimer’s disease and epilepsy[J]. Neurobiol Aging, 2014, 35(9): 2091–2095

[232] Savage JC, Jay T, Goduni E, Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease[J]. J Neurosci, 2015, 35(16): 6532–6543

[233] Kuntz M, Candela P, Saint-Pol J, Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier[J]. J Alzheimers Dis, 2015, 48(3): 849–862

[234] Schweinzer C, Kober A, Lang I, Processing of endogenous AβPP in blood-brain barrier endothelial cells is modulated by liver-X receptor agonists and altered cellular cholesterol homeostasis[J]. J Alzheimers Dis, 2011, 27(2): 341–360

[235] Wang S, Wen P, Wood S. Effect of LXR/RXR agonism on brain and CSF Aβ40 levels in rats[J]. F1000Res, 2016, 5: 138

[236] Cummings JL, Zhong K, Kinney JW, Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease[J]. Alzheimers Res Ther, 2016, 8: 4

[237] Pierrot N, Lhommel R, Quenon L, Targretin improves cognitive and biological markers in a patient with Alzheimer’s disease[J]. J Alzheimers Dis, 2016, 49(2): 271–276

[238] Niesor EJ, Schwartz GG, Perez A, Statin-induced decrease in ATP-binding cassette transporter A1 expression via microRNA33 induction may counteract cholesterol efflux to high-density lipoprotein[J]. Cardiovasc Drugs Ther, 2015, 29(1): 7–14

[239] Rached F, Lhomme M, Camont L, Defective functionality of small, dense HDL3 subpopulations in ST segment elevation myocardial infarction: Relevance of enrichment in lysophosphatidylcholine, phosphatidic acid and serum amyloid A[J]. Biochim Biophys Acta- Mol Cell Biol Lipids 2015; 1851: 1254–1261.

[240] Papathanasiou A, Kostara C, Cung MT, Analysis of the composition of plasma lipoproteins in patients with extensive coronary heart disease using 1H NMR spectroscopy[J]. Hellenic J Cardiol, 2008, 49(2): 72–78

[241] Ozerova IN, Perova NV, Shchel’tsyna NV, Parameters of high-density lipoproteins in patients with arterial hypertension in combination with other components of metabolic syndrome[J]. Bull Exp Biol Med, 2007, 143(3): 320–322

[242] Ross DJ, Hough G, Hama S, Proinflammatory high-density lipoprotein results from oxidized lipid mediators in the pathogenesis of both idiopathic and associated types of pulmonary arterial hypertension[J]. Pulm Circ, 2015, 5(4): 640–648

[243] Pruzanski W, Stefanski E, de Beer FC, Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins[J]. J Lipid Res, 2000, 41(7): 1035–1047

[244] Honda H, Hirano T, Ueda M, High-Density Lipoprotein Subfractions and Their Oxidized Subfraction Particles in Patients with Chronic Kidney Disease[J]. J Atheroscler Thromb, 2016, 23(1): 81–94

[245] Berrougui H, Isabelle M, Cloutier M, Age-related impairment of HDL-mediated cholesterol efflux[J]. J Lipid Res, 2007, 48(2): 328–336

[246] Parra S, Castro A, Masana L. The pleiotropic role of HDL in autoimmune diseases[J]. Clin Investig Arterioscler, 2015, 27(2): 97–106

[247] McMahon M, Grossman J, FitzGerald J, Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis[J]. Arthritis Rheum, 2006, 54(8): 2541–2549

[248] Perségol L, Vergès B, Gambert P, Inability of HDL from abdominally obese subjects to counteract the inhibitory effect of oxidized LDL on vasorelaxation[J]. J Lipid Res, 2007, 48(6): 1396–1401

[249] Khalil A, Berrougui H, Pawelec G, Impairment of the ABCA1 and SR-BI-mediated cholesterol efflux pathways and HDL anti-inflammatory activity in Alzheimer’s disease[J]. Mech Ageing Dev, 2012, 133(1): 20–29

[250] Pertl L, Kern S, Weger M, High-density lipoprotein function in exudative age-related macular degeneration[J]. PLoS One, 2016, 11: 1–14.

RIGHTS & PERMISSIONS

2017 2017 by the Journal of Biomedical Research.