Associations between atherosclerosis and neurological diseases, beyond ischemia-induced cerebral damage

  • Dannia Colín-CastelánEmail author
  • Silvio Zaina


Neurodegeneration is traditionally viewed as a consequence of peptide accumulation in the brain, stroke and/or cerebral ischemia. Nonetheless, a number of scattered observations suggest that neurological disease and atherosclerosis may be linked by more complex mechanisms. Understanding the intricate link between atherosclerosis and neurological conditions may have a significant impact on the quality of life of the growing ageing population and of high cardiovascular risk groups in general. Epidemiological data support the notion that neurological dysfunction and atherosclerosis coexist long before any evident clinical complications of cardiovascular disease appear and may be causally linked. Baffling, often overlooked, molecular data suggest that nervous tissue-specific gene expression is relaxed specifically in the atheromatous vascular wall, and/or that a systemic dysregulation of genes involved in nervous system biology dictates a concomitant progression of neurological disease and atherosclerosis. Further epidemiological and experimental work is needed to clarify the details and clinical relevance of those complex links.


Atherosclerosis Neurodegeneration Ischemia Gene expression Endothelial dysfunction 



D. Colín-Castelán was supported by a Consejo Nacional de Ciencia y Tecnología (CONACyT, Mexico) Postdoctoral Fellowship no. 2018-000005-01NACV-00163, within the “Estancias Posdoctorales Vinculadas al Fortalecimiento de la Calidad del Posgrado Nacional” program.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Tosto G, Bird TD, Bennett DA, Boeve BF, Brickman AM, Cruchaga C, et al. The role of cardiovascular risk factors and stroke in familial Alzheimer disease. JAMA Neurol. 2016;73(10):1231–7. Scholar
  2. 2.
    Cermakova P, Eriksdotter M, Lund LH, Winblad B, Religa P, Religa D. Heart failure and Alzheimer's disease. J Intern Med. 2015;277(4):406–25. Scholar
  3. 3.
    Polidori MC, Mariani E, Mecocci P, Nelles G. Congestive heart failure and Alzheimer's disease. Neurol Res. 2006;28(6):588–94. Scholar
  4. 4.
    Alves TC, Busatto GF. Regional cerebral blood flow reductions, heart failure and Alzheimer's disease. Neurol Res. 2006;28(6):579–87. Scholar
  5. 5.
    Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res. 2017;95(4):943–72. Scholar
  6. 6.
    Bornstein NM, Halevy G, Treves T, Korczyn AD. Cerebral atherosclerosis in parkinsonian patients. Parkinsonism Relat Disord. 1998;4(2):87–90.Google Scholar
  7. 7.
    Perju-Dumbrava L, Muntean ML, Muresanu DF. Cerebrovascular profile assessment in Parkinson's disease patients. CNS Neurol Disord Drug Targets. 2014;13(4):712–7.Google Scholar
  8. 8.
    Chen WH, Jin W, Lyu PY, Liu Y, Li R, Hu M, et al. Carotid atherosclerosis and cognitive impairment in nonstroke patients. Chin Med J. 2017;130(19):2375–9. Scholar
  9. 9.
    Dolan H, Crain B, Troncoso J, Resnick SM, Zonderman AB, Obrien RJ. Atherosclerosis, dementia, and Alzheimer disease in the Baltimore longitudinal study of aging cohort. Ann Neurol. 2010;68(2):231–40. Scholar
  10. 10.
    Deschaintre Y, Richard F, Leys D, Pasquier F. Treatment of vascular risk factors is associated with slower decline in Alzheimer disease. Neurology. 2009;73(9):674–80. Scholar
  11. 11.
    Geifman N, Brinton RD, Kennedy RE, Schneider LS, Butte AJ. Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer's disease. Alzheimers Res Ther. 2017;9(1):10. Scholar
  12. 12.
    Niu H, Álvarez-Álvarez I, Guillén-Grima F, Aguinaga-Ontoso I. Prevalence and incidence of Alzheimer’s disease in Europe: a meta-analysis. Neurologia. 2017;8(32):523–32.Google Scholar
  13. 13.
    Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, et al. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003;157(11):1015–22.Google Scholar
  14. 14.
    Alzheimer's A. 2015 Alzheimer's disease facts and figures. Alzheimers Dement. 2015;11(3):332–84.Google Scholar
  15. 15.
    Sahay S, Ghosh D, Singh PK, Maji SK. Alteration of structure and aggregation of alpha-Synuclein by familial Parkinson's disease associated mutations. Curr Protein Pept Sci. 2017;18(7):656–76. Scholar
  16. 16.
    Flagmeier P, Meisl G, Vendruscolo M, Knowles TP, Dobson CM, Buell AK, et al. Mutations associated with familial Parkinson's disease alter the initiation and amplification steps of alpha-synuclein aggregation. Proc Natl Acad Sci U S A. 2016;113(37):10328–33. Scholar
  17. 17.
    Spivey A. Rotenone and paraquat linked to Parkinson's disease: human exposure study supports years of animal studies. Environ Health Perspect. 2011;119(6):A259. Scholar
  18. 18.
    Drożdżyński D, Kowalska J. Rapid analysis of organic farming insecticides in soil and produce using ultra-performance liquid chromatography/tandem mass spectrometry. Anal Bioanal Chem. 2009;394(8):2241–7. Scholar
  19. 19.
    Qi Z, Miller GW, Voit EO. Rotenone and paraquat perturb dopamine metabolism: a computational analysis of pesticide toxicity. Toxicology. 2014;315:92–101. Scholar
  20. 20.
    Nistico R, Mehdawy B, Piccirilli S, Mercuri N. Paraquat- and rotenone-induced models of Parkinson's disease. Int J Immunopathol Pharmacol. 2011;24(2):313–22. Scholar
  21. 21.
    Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, et al. Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect. 2011;119(6):866–72. Scholar
  22. 22.
    Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke Statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603. Scholar
  23. 23.
    Seidell JC, Halberstadt J. The global burden of obesity and the challenges of prevention. Ann Nutr Metab. 2015;66(Suppl 2):7–12. Scholar
  24. 24.
    Thompson RC, Allam AH, Lombardi GP, Wann LS, Sutherland ML, Sutherland JD, et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet. 2013;381(9873):1211–22. Scholar
  25. 25.
    Palombo C, Kozakova M. Arterial stiffness, atherosclerosis and cardiovascular risk: pathophysiologic mechanisms and emerging clinical indications. Vasc Pharmacol. 2016;77:1–7. Scholar
  26. 26.
    Gomez-Hernandez A, Beneit N, Diaz-Castroverde S, Escribano O. Differential role of adipose tissues in obesity and related metabolic and vascular complications. Int J Endocrinol. 2016;2016:1216783–15. Scholar
  27. 27.
    Al Rifai M, Silverman MG, Nasir K, Budoff MJ, Blankstein R, Szklo M, et al. The association of nonalcoholic fatty liver disease, obesity, and metabolic syndrome, with systemic inflammation and subclinical atherosclerosis: the Multi-Ethnic Study Of atherosclerosis (MESA). Atherosclerosis. 2015;239(2):629–33. Scholar
  28. 28.
    Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol. 2009;6(6):399–409. Scholar
  29. 29.
    Guzik TJ, Skiba DS, Touyz RM, Harrison DG. The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res. 2017;113(9):1009–23. Scholar
  30. 30.
    Bischof GN, Park DC. Obesity and aging: consequences for cognition, brain structure, and brain function. Psychosom Med. 2015;77(6):697–709. Scholar
  31. 31.
    Debette S, Seshadri S, Beiser A, Au R, Himali JJ, Palumbo C, et al. Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology. 2011;77(5):461–8. Scholar
  32. 32.
    Stewart R, Masaki K, Xue QL, Peila R, Petrovitch H, White LR, et al. A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia aging study. Arch Neurol. 2005;62(1):55–60. Scholar
  33. 33.
    Bednarska-Makaruk M, Graban A, Wisniewska A, Lojkowska W, Bochynska A, Gugala-Iwaniuk M, et al. Association of adiponectin, leptin and resistin with inflammatory markers and obesity in dementia. Biogerontology. 2017;18(4):561–80. Scholar
  34. 34.
    Kullmann S, Callaghan MF, Heni M, Weiskopf N, Scheffler K, Haring HU, et al. Specific white matter tissue microstructure changes associated with obesity. Neuroimage. 2016;125:36–44. Scholar
  35. 35.
    van Bloemendaal L, Ijzerman RG, Ten Kulve JS, Barkhof F, Diamant M, Veltman DJ, et al. Alterations in white matter volume and integrity in obesity and type 2 diabetes. Metab Brain Dis. 2016;31(3):621–9. Scholar
  36. 36.
    Nouwen A, Chambers A, Chechlacz M, Higgs S, Blissett J, Barrett TG, et al. Microstructural abnormalities in white and gray matter in obese adolescents with and without type 2 diabetes. Neuroimage Clin. 2017;16:43–51. Scholar
  37. 37.
    Tuulari JJ, Karlsson HK, Antikainen O, Hirvonen J, Pham T, Salminen P, et al. Bariatric surgery induces White and Grey matter density recovery in the morbidly obese: a voxel-based morphometric study. Hum Brain Mapp. 2016;37(11):3745–56. Scholar
  38. 38.
    Bond DJ, Silveira LE, MacMillan EL, Torres IJ, Lang DJ, Su W, et al. Diagnosis and body mass index effects on hippocampal volumes and neurochemistry in bipolar disorder. Transl Psychiatry. 2017;7(3):e1071. Scholar
  39. 39.
    Hidese S, Ota M, Matsuo J, Ishida I, Hiraishi M, Yoshida S, et al. Association of obesity with cognitive function and brain structure in patients with major depressive disorder. J Affect Disord. 2018;225:188–94. Scholar
  40. 40.
    Gustafson DR, Karlsson C, Skoog I, Rosengren L, Lissner L, Blennow K. Mid-life adiposity factors relate to blood-brain barrier integrity in late life. J Intern Med. 2007;262(6):643–50. Scholar
  41. 41.
    Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 2014;69(10):1212–26. Scholar
  42. 42.
    Schnaider Beeri M, Goldbourt U, Silverman JM, Noy S, Schmeidler J, Ravona-Springer R, et al. Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology. 2004;63(10):1902–7.Google Scholar
  43. 43.
    Young SE, Mainous AG 3rd, Carnemolla M. Hyperinsulinemia and cognitive decline in a middle-aged cohort. Diabetes Care. 2006;29(12):2688–93. Scholar
  44. 44.
    Nazaribadie M, Amini M, Ahmadpanah M, Asgari K, Jamlipaghale S, Nazaribadie S. Executive functions and information processing in patients with type 2 diabetes in comparison to pre-diabetic patients. J Diabetes Metab Disord. 2014;13(1):27. Scholar
  45. 45.
    Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology. 2010;75(13):1195–202. Scholar
  46. 46.
    Schneider ALC, Selvin E, Sharrett AR, Griswold M, Coresh J, Jack CR Jr, et al. Diabetes, prediabetes, and brain volumes and subclinical cerebrovascular disease on MRI: the atherosclerosis risk in communities neurocognitive study (ARIC-NCS). Diabetes Care. 2017;40(11):1514–21. Scholar
  47. 47.
    Katakami N. Mechanism of development of atherosclerosis and cardiovascular disease in diabetes mellitus. J Atheroscler Thromb. 2018;25(1):27–39. Scholar
  48. 48.
    Domingueti CP, Dusse LM, Carvalho M, de Sousa LP, Gomes KB, Fernandes AP. Diabetes mellitus: the linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J Diabetes Complicat. 2016;30(4):738–45. Scholar
  49. 49.
    Wang HH, Garruti G, Liu M, Portincasa P, Wang DQ. Cholesterol and lipoprotein metabolism and atherosclerosis: recent advances in reverse cholesterol transport. Ann Hepatol. 2017;16(Suppl. 1: s3-105):s27–42. Scholar
  50. 50.
    Hurtubise J, McLellan K, Durr K, Onasanya O, Nwabuko D, Ndisang JF. The different facets of dyslipidemia and hypertension in atherosclerosis. Curr Atheroscler Rep. 2016;18(12):82. Scholar
  51. 51.
    Reitz C. Dyslipidemia and the risk of Alzheimer's disease. Curr Atheroscler Rep. 2013;15(3):307. Scholar
  52. 52.
    Magnan C, Levin BE, Luquet S. Brain lipid sensing and the neural control of energy balance. Mol Cell Endocrinol. 2015;418 Pt 1:3–8. Scholar
  53. 53.
    Xie F, Fu H, Hou JF, Jiao K, Costigan M, Chen J. High energy diets-induced metabolic and prediabetic painful polyneuropathy in rats. PLoS One. 2013;8(2):e57427. Scholar
  54. 54.
    Bjorkhem I. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med. 2006;260(6):493–508. Scholar
  55. 55.
    Yang W, Shi H, Zhang J, Shen Z, Zhou G, Hu M. Effects of the duration of hyperlipidemia on cerebral lipids, vessels and neurons in rats. Lipids Health Dis. 2017;16(1):26. Scholar
  56. 56.
    Paul R, Choudhury A, Chandra Boruah D, Devi R, Bhattacharya P, Choudhury MD, et al. Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: relevance to Parkinson's disease. Neurochem Int. 2017;108:15–26. Scholar
  57. 57.
    Ohwaki K, Yano E, Tamura A, Inoue T, Saito I. Hypercholesterolemia is associated with a lower risk of cerebral ischemic small vessel disease detected on brain checkups. Clin Neurol Neurosurg. 2013;115(6):669–72. Scholar
  58. 58.
    Zhu L, Zhong M, Elder GA, Sano M, Holtzman DM, Gandy S, et al. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A. 2015;112(38):11965–70. Scholar
  59. 59.
    Hostage CA, Roy Choudhury K, Doraiswamy PM, Petrella JR, Alzheimer's Disease Neuroimaging I. Dissecting the gene dose-effects of the APOE epsilon4 and epsilon2 alleles on hippocampal volumes in aging and Alzheimer's disease. PLoS One. 2013;8(2):e54483. Scholar
  60. 60.
    Liu M, Bian C, Zhang J, Wen F. Apolipoprotein E gene polymorphism and Alzheimer's disease in Chinese population: a meta-analysis. Sci Rep. 2014;4:4383. Scholar
  61. 61.
    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523–7. Scholar
  62. 62.
    Tambini MD, Pera M, Kanter E, Yang H, Guardia-Laguarta C, Holtzman D, et al. ApoE4 upregulates the activity of mitochondria-associated ER membranes. EMBO Rep. 2016;17(1):27–36. Scholar
  63. 63.
    Hafezi-Moghadam A, Thomas KL, Wagner DD. ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. Am J Phys Cell Phys. 2007;292(4):C1256–62. Scholar
  64. 64.
    Janssen CI, Jansen D, Mutsaers MP, Dederen PJ, Geenen B, Mulder MT, et al. The effect of a high-fat diet on brain plasticity, inflammation and cognition in female ApoE4-Knockin and ApoE-knockout mice. PLoS One. 2016;11(5):e0155307. Scholar
  65. 65.
    Lusis AJ. Genetics of atherosclerosis. Trends Genet. 2012;28(6):267–75. Scholar
  66. 66.
    Stylianou IM, Bauer RC, Reilly MP, Rader DJ. Genetic basis of atherosclerosis: insights from mice and humans. Circ Res. 2012;110(2):337–55. Scholar
  67. 67.
    McPherson R, Tybjaerg-Hansen A. Genetics of coronary artery disease. Circ Res. 2016;118(4):564–78. Scholar
  68. 68.
    Benn M, Nordestgaard BG, Frikke-Schmidt R, Tybjaerg-Hansen A. Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study. BMJ. 2017;357:j1648. Scholar
  69. 69.
    Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol. 2007;14(5):413–9. Scholar
  70. 70.
    Lachman S, Boekholdt SM, Luben RN, Sharp SJ, Brage S, Khaw KT, et al. Impact of physical activity on the risk of cardiovascular disease in middle-aged and older adults: EPIC Norfolk prospective population study. Eur J Prev Cardiol. 2018;25(2):200–8. Scholar
  71. 71.
    Ertek S, Cicero A. Impact of physical activity on inflammation: effects on cardiovascular disease risk and other inflammatory conditions. Arch Med Sci. 2012;8(5):794–804. Scholar
  72. 72.
    Pedersen BK. Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. Eur J Clin Investig. 2017;47(8):600–11. Scholar
  73. 73.
    Krauss J, Farzaneh-Far R, Puterman E, Na B, Lin J, Epel E, et al. Physical fitness and telomere length in patients with coronary heart disease: findings from the heart and soul study. PLoS One. 2011;6(11):e26983. Scholar
  74. 74.
    LaRocca TJ, Seals DR, Pierce GL. Leukocyte telomere length is preserved with aging in endurance exercise-trained adults and related to maximal aerobic capacity. Mech Ageing Dev. 2010;131(2):165–7. Scholar
  75. 75.
    Rossman MJ, Kaplon RE, Hill SD, McNamara MN, Santos-Parker JR, Pierce GL, et al. Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function. Am J Phys Heart Circ Phys. 2017;313(5):H890–H5. Scholar
  76. 76.
    McClean C, Harris RA, Brown M, Brown JC, Davison GW. Effects of exercise intensity on postexercise endothelial function and oxidative stress. Oxidative Med Cell Longev. 2015;2015:723679–8. Scholar
  77. 77.
    Hamer M, Chida Y. Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med. 2009;39(1):3–11. Scholar
  78. 78.
    Huttenrauch M, Brauss A, Kurdakova A, Borgers H, Klinker F, Liebetanz D, et al. Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model. Transl Psychiatry. 2016;6:e800. Scholar
  79. 79.
    Alvarez-Lopez MJ, Castro-Freire M, Cosin-Tomas M, Sanchez-Roige S, Lalanza JF, Del Valle J, et al. Long-term exercise modulates hippocampal gene expression in senescent female mice. J Alzheimers Dis. 2013;33(4):1177–90. Scholar
  80. 80.
    Duncombe J, Kitamura A, Hase Y, Ihara M, Kalaria RN, Horsburgh K. Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia. Clin Sci (Lond). 2017;131(19):2451–68. Scholar
  81. 81.
    Salvadores N, Searcy JL, Holland PR, Horsburgh K. Chronic cerebral hypoperfusion alters amyloid-beta peptide pools leading to cerebral amyloid angiopathy, microinfarcts and haemorrhages in Tg-SwDI mice. Clin Sci (Lond). 2017;131(16):2109–23. Scholar
  82. 82.
    Patel A, Moalem A, Cheng H, Babadjouni RM, Patel K, Hodis DM, et al. Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice. Neurol Res. 2017;39(10):910–7. Scholar
  83. 83.
    Hunt BJ, Jurd KM. Endothelial cell activation. A central pathophysiological process. BMJ. 1998;316(7141):1328–9.Google Scholar
  84. 84.
    Hughes CG, Pandharipande PP, Thompson JL, Chandrasekhar R, Ware LB, Ely EW, et al. Endothelial activation and blood-brain barrier injury as risk factors for delirium in critically ill patients*. Crit Care Med. 2016;44(9):e809–e17. Scholar
  85. 85.
    Gurney KJ, Estrada EY, Rosenberg GA. Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation. Neurobiol Dis. 2006;23(1):87–96. Scholar
  86. 86.
    Kirk J, Plumb J, Mirakhur M, McQuaid S. Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J Pathol. 2003;201(2):319–27. Scholar
  87. 87.
    Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–19. Scholar
  88. 88.
    Kayed R, Lasagna-Reeves CA. Molecular mechanisms of amyloid oligomers toxicity. J Alzheimers Dis. 2013;33(Suppl 1):S67–78. Scholar
  89. 89.
    Bardai FH, Wang L, Mutreja Y, Yenjerla M, Gamblin TC, Feany MB. A conserved cytoskeletal signaling Cascade mediates neurotoxicity of FTDP-17 tau mutations in vivo. J Neurosci. 2018;38(1):108–19. Scholar
  90. 90.
    Burre J, Sharma M, Sudhof TC. Definition of a molecular pathway mediating alpha-synuclein neurotoxicity. J Neurosci. 2015;35(13):5221–32. Scholar
  91. 91.
    Garbuzova-Davis S, Hernandez-Ontiveros DG, Rodrigues MC, Haller E, Frisina-Deyo A, Mirtyl S, et al. Impaired blood-brain/spinal cord barrier in ALS patients. Brain Res. 2012;1469:114–28. Scholar
  92. 92.
    Yamazaki Y, Kanekiyo T. Blood-brain barrier dysfunction and the pathogenesis of Alzheimer's disease. Int J Mol Sci. 2017;18(9).
  93. 93.
    Gray MT, Woulfe JM. Striatal blood-brain barrier permeability in Parkinson's disease. J Cereb Blood Flow Metab. 2015;35(5):747–50. Scholar
  94. 94.
    Cramer SP, Modvig S, Simonsen HJ, Frederiksen JL, Larsson HB. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis. Brain. 2015;138(Pt 9):2571–83. Scholar
  95. 95.
    Ujiie M, Dickstein DL, Carlow DA, Jefferies WA. Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation. 2003;10(6):463–70. Scholar
  96. 96.
    van de Haar HJ, Burgmans S, Jansen JF, van Osch MJ, van Buchem MA, Muller M, et al. Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology. 2016;281(2):527–35. Scholar
  97. 97.
    Chistiakov DA, Orekhov AN, Bobryshev YV. Contribution of neovascularization and intraplaque haemorrhage to atherosclerotic plaque progression and instability. Acta Physiol (Oxford). 2015;213(3):539–53. Scholar
  98. 98.
    Moreno PR, Purushothaman KR, Fuster V, Echeverri D, Truszczynska H, Sharma SK, et al. Plaque neovascularization is increased in ruptured atherosclerotic lesions of human Aorta. Circulation. 2004;110(14):2032–8. Scholar
  99. 99.
    Ding X, Gu R, Zhang M, Ren H, Shu Q, Xu G, et al. Microglia enhanced the angiogenesis, migration and proliferation of co-cultured RMECs. BMC Ophthalmol. 2018;18(1):249. Scholar
  100. 100.
    Schultheiss C, Blechert B, Gaertner FC, Drecoll E, Mueller J, Weber GF, et al. In vivo characterization of endothelial cell activation in a transgenic mouse model of Alzheimer's disease. Angiogenesis. 2006;9(2):59–65. Scholar
  101. 101.
    Desai BS, Schneider JA, Li JL, Carvey PM, Hendey B. Evidence of angiogenic vessels in Alzheimer's disease. J Neural Transm (Vienna). 2009;116(5):587–97. Scholar
  102. 102.
    Yang SP, Bae DG, Kang HJ, Gwag BJ, Gho YS, Chae CB. Co-accumulation of vascular endothelial growth factor with beta-amyloid in the brain of patients with Alzheimer's disease. Neurobiol Aging. 2004;25(3):283–90. Scholar
  103. 103.
    Janelidze S, Lindqvist D, Francardo V, Hall S, Zetterberg H, Blennow K, et al. Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology. 2015;85(21):1834–42. Scholar
  104. 104.
    Ryu JK, McLarnon JG. Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-alpha in an animal model of inflamed Alzheimer's disease brain. Neurobiol Dis. 2008;29(2):254–66. Scholar
  105. 105.
    Palencia G, Garcia E, Osorio-Rico L, Trejo-Solis C, Escamilla-Ramirez A, Sotelo J. Neuroprotective effect of thalidomide on MPTP-induced toxicity. Neurotoxicology. 2015;47:82–7. Scholar
  106. 106.
    Kitaguchi H, Ihara M, Saiki H, Takahashi R, Tomimoto H. Capillary beds are decreased in Alzheimer's disease, but not in Binswanger's disease. Neurosci Lett. 2007;417(2):128–31. Scholar
  107. 107.
    Villar-Cheda B, Sousa-Ribeiro D, Rodriguez-Pallares J, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL. Aging and sedentarism decrease vascularization and VEGF levels in the rat substantia nigra. Implications for Parkinson's disease. J Cereb Blood Flow Metab. 2009;29(2):230–4. Scholar
  108. 108.
    Yang P, Min X-L, Mohammadi M, Turner C, Faull R, Waldvogel H, et al. Endothelial degeneration of parkinson’s disease is related to alpha-synuclein aggregation. J Alzheimers Dis Parkinsonism. 2017;7(5).
  109. 109.
    Zacchigna S, Lambrechts D, Carmeliet P. Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci. 2008;9(3):169–81. Scholar
  110. 110.
    Colin-Castelan D, Phillips-Farfan BV, Gutierrez-Ospina G, Fuentes-Farias AL, Baez-Saldana A, Padilla-Cortes P, et al. EphB4 is developmentally and differentially regulated in blood vessels throughout the forebrain neurogenic niche in the mouse brain: implications for vascular remodeling. Brain Res. 2011;1383:90–8. Scholar
  111. 111.
    Meléndez-Herrera E, Colín-Castelán D, Varela-Echavarría A, Gutiérrez-Ospina G. Semaphorin-3A and its receptor neuropilin-1 are predominantly expressed in endothelial cells along the rostral migratory stream of young and adult mice. Cell Tissue Res. 2008;333(2):175–84. Scholar
  112. 112.
    Cantarella G, Lempereur L, Presta M, Ribatti D, Lombardo G, Lazarovici P, et al. Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo. FASEB J. 2002;16(10):1307–9. Scholar
  113. 113.
    Cunningham LA, Candelario K, Li L. Roles for HIF-1alpha in neural stem cell function and the regenerative response to stroke. Behav Brain Res. 2012;227(2):410–7. Scholar
  114. 114.
    Delgado Ana C, Ferrón Sacri R, Vicente D, Porlan E, Perez-Villalba A, Trujillo Carmen M, et al. Endothelial NT-3 delivered by vasculature and CSF promotes quiescence of subependymal neural stem cells through nitric oxide induction. Neuron. 2014;83(3):572–85. Scholar
  115. 115.
    Usui T, Naruo A, Okada M, Hayabe Y, Yamawaki H. Brain-derived neurotrophic factor promotes angiogenic tube formation through generation of oxidative stress in human vascular endothelial cells. Acta Physiol (Oxford). 2014;211(2):385–94. Scholar
  116. 116.
    Li S, Haigh K, Haigh JJ, Vasudevan A. Endothelial VEGF sculpts cortical cytoarchitecture. J Neurosci. 2013;33(37):14809–15. Scholar
  117. 117.
    Erskine L, Francois U, Denti L, Joyce A, Tillo M, Bruce F, et al. VEGF-A and neuropilin 1 (NRP1) shape axon projections in the developing CNS via dual roles in neurons and blood vessels. Development. 2017;144(13):2504–16. Scholar
  118. 118.
    Masuda T, Taniguchi M. Contribution of semaphorins to the formation of the peripheral nervous system in higher vertebrates. Cell Adhes Migr. 2016;10(6):593–603. Scholar
  119. 119.
    Fiore R, Puschel AW. The function of semaphorins during nervous system development. Front Biosci. 2003;8:s484–99.Google Scholar
  120. 120.
    Tillo M, Ruhrberg C, Mackenzie F. Emerging roles for semaphorins and VEGFs in synaptogenesis and synaptic plasticity. Cell Adhes Migr. 2012;6(6):541–6. Scholar
  121. 121.
    Ng T, Ryu JR, Sohn JH, Tan T, Song H, Ming G-L, et al. Class 3 Semaphorin Mediates Dendrite Growth in Adult Newborn Neurons through Cdk5/FAK Pathway. PLoS ONE. 2013;8(6):e65572. Scholar
  122. 122.
    Segarra M, Ohnuki H, Maric D, Salvucci O, Hou X, Kumar A, et al. Semaphorin 6A regulates angiogenesis by modulating VEGF signaling. Blood. 2012;120(19):4104–15. Scholar
  123. 123.
    Erber R, Eichelsbacher U, Powajbo V, Korn T, Djonov V, Lin J, et al. EphB4 controls blood vascular morphogenesis during postnatal angiogenesis. EMBO J. 2006;25(3):628–41. Scholar
  124. 124.
    Swift MR, Weinstein BM. Arterial-venous specification during development. Circ Res. 2009;104(5):576–88. Scholar
  125. 125.
    Shu Y, Xiao B, Wu Q, Liu T, Du Y, Tang H, et al. The Ephrin-A5/EphA4 interaction modulates neurogenesis and angiogenesis by the p-Akt and p-ERK pathways in a mouse model of TLE. Mol Neurobiol. 2016;53(1):561–76. Scholar
  126. 126.
    Koyanagi I, Akers KG, Vergara P, Srinivasan S, Sakurai T, Sakaguchi M. Memory consolidation during sleep and adult hippocampal neurogenesis. Neural Regen Res. 2019;14(1):20–3. Scholar
  127. 127.
    McAvoy K, Besnard A, Sahay A. Adult hippocampal neurogenesis and pattern separation in DG: a role for feedback inhibition in modulating sparseness to govern population-based coding. Front Syst Neurosci. 2015;9:120. Scholar
  128. 128.
    Hollands C, Tobin MK, Hsu M, Musaraca K, Yu TS, Mishra R, et al. Depletion of adult neurogenesis exacerbates cognitive deficits in Alzheimer's disease by compromising hippocampal inhibition. Mol Neurodegener. 2017;12(1):64. Scholar
  129. 129.
    Jin H, Chen Y, Wang B, Zhu Y, Chen L, Han X, et al. Association between brain-derived neurotrophic factor and von Willebrand factor levels in patients with stable coronary artery disease. BMC Cardiovasc Disord. 2018;18(1):23. Scholar
  130. 130.
    Nehme A, Kobeissy F, Zhao J, Zhu R, Feugier P, Mechref Y, et al. Functional pathways associated with human carotid atheroma: a proteomics analysis. Hypertens Res. 2019;42(3):362–73. Scholar
  131. 131.
    Rangel-Salazar R, Wickstrom-Lindholm M, Aguilar-Salinas CA, Alvarado-Caudillo Y, Dossing KB, Esteller M, et al. Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages. BMC Genomics. 2011;12:582. Scholar
  132. 132.
    Furigo IC, Melo HM, Lyra ESNM, Ramos-Lobo AM, Teixeira PDS, Buonfiglio DC, et al. Brain STAT5 signaling modulates learning and memory formation. Brain Struct Funct. 2018;223(5):2229–41. Scholar
  133. 133.
    Shim KS, Ferrando-Miguel R, Lubec G. Aberrant protein expression of transcription factors BACH1 and ERG, both encoded on chromosome 21, in brains of patients with down syndrome and Alzheimer's disease. J Neural Transm Suppl. 2003;67:39–49.Google Scholar
  134. 134.
    Di Domenico F, Pupo G, Mancuso C, Barone E, Paolini F, Arena A, et al. Bach1 overexpression in down syndrome correlates with the alteration of the HO-1/BVR-a system: insights for transition to Alzheimer's disease. J Alzheimers Dis. 2015;44(4):1107–20. Scholar
  135. 135.
    Losing P, Niturad CE, Harrer M, Reckendorf CMZ, Schatz T, Sinske D, et al. SRF modulates seizure occurrence, activity induced gene transcription and hippocampal circuit reorganization in the mouse pilocarpine epilepsy model. Mol Brain. 2017;10(1):30. Scholar
  136. 136.
    Zaina S, Heyn H, Carmona FJ, Varol N, Sayols S, Condom E, et al. DNA methylation map of human atherosclerosis. Circ Cardiovasc Genet. 2014;7(5):692–700. Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical Sciences, Division of Health Sciences, Campus LeónUniversity of GuanajuatoLeónMexico

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