Analysis of endothelial gene polymorphisms in Spanish patients with vascular dementia and Alzheimer´s disease.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 08 2023
18 08 2023
Historique:
received:
30
09
2019
accepted:
14
10
2020
medline:
21
8
2023
pubmed:
19
8
2023
entrez:
18
8
2023
Statut:
epublish
Résumé
There is increasing evidence for the involvement of blood-brain barrier (BBB) in vascular dementia (VaD) and Alzheimer´s disease (AD) pathogenesis. However, the role of endothelial function-related genes in these disorders remains unclear. We evaluated the association of four single-nucleotide polymorphisms (VEGF, VEGFR2 and NOS3) with diagnosis and rate of cognitive decline in AD and VaD in a Spanish case-control cohort (150 VaD, 147 AD and 150 controls). Participants carrying -604AA genotype in VEGFR2 (rs2071559) were less susceptible to VaD after multiple testing. Further analysis for VaD subtype revealed a significant difference between small-vessel VaD patients and controls, but not for large-vessel VaD patients. In addition, -2578A and -460C alleles in VEGF (rs699947 and rs833061) showed to decrease the risk of AD, whereas NOS3 (rs1799983) influenced disease progression. Our study supports previous findings of a deleterious effect of VEGFR2 reduced expression on small-vessel disease, but not on large-vessel disease; as well as a detrimental effect of down-regulating VEGF and eNOS in AD, affecting vascular permeability and neuronal survival. These data highlight the relevance of endothelial function and, therefore, BBB in both VaD and AD.
Identifiants
pubmed: 37596325
doi: 10.1038/s41598-023-39576-7
pii: 10.1038/s41598-023-39576-7
pmc: PMC10439194
doi:
Substances chimiques
Vascular Endothelial Growth Factor A
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13441Informations de copyright
© 2023. Springer Nature Limited.
Références
Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).
pubmed: 16461860
doi: 10.1001/archpsyc.63.2.168
Gorelick, P.B., et al; American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Vascular contributions to cognitive impairment and dementia: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2, 2672–2713 (2011).
Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).
pubmed: 8346443
doi: 10.1126/science.8346443
Manso-Calderón, R. & González-Sarmiento, R. Genetic susceptibility to vascular cognitive impairment: A pathophysiological view. Fut. Neurol. 11, 119–134 (2016).
doi: 10.2217/fnl-2016-0002
Ikram, M. A. et al. Genetics of vascular dementia–review from the ICVD working group. BMC Med. 15, 48. https://doi.org/10.1186/s12916-017-0813-9 (2017).
doi: 10.1186/s12916-017-0813-9
pubmed: 28260527
pmcid: 5338082
Hachinski, V. et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 37, 2220–2241 (2006).
pubmed: 16917086
doi: 10.1161/01.STR.0000237236.88823.47
Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).
pubmed: 18215617
doi: 10.1016/j.neuron.2008.01.003
Stanimirovic, D. B. & Friedman, A. Pathophysiology of the neurovascular unit: Disease cause or consequence?. J. Cereb. Blood Flow Metab. 32, 1207–1221 (2012).
pubmed: 22395208
pmcid: 3390807
doi: 10.1038/jcbfm.2012.25
Enciu, A. M., Constantinescu, S. N., Popescu, L. M., Mureşanu, D. F. & Popescu, B. O. Neurobiology of vascular dementia. J Aging Res 2011, 401604. https://doi.org/10.4061/2011/401604 (2011).
doi: 10.4061/2011/401604
pubmed: 21876809
pmcid: 3160011
Provias, J. & Jeynes, B. Neurofibrillary tangles and senile plaques in Alzheimer´s brains are associated with reduced capillary expression of vascular endothelial growth factor and endothelial nitric oxide synthase. Curr. Neurovasc. Res. 5, 199–205 (2008).
pubmed: 18691078
doi: 10.2174/156720208785425729
Hermann, D. M. & Zechariah, A. Implications of vascular endothelial growth factor for postischemic neurovascular remodeling. J. Cereb Blood Flow Metab. 29, 1620–1643 (2009).
pubmed: 19654590
doi: 10.1038/jcbfm.2009.100
Moro, M. A., Cárdenas, A., Hurtado, O., Leza, J. C. & Lizasoain, I. Role of nitric oxide after brain ischaemia. Cell Calcium 36, 265–275 (2004).
pubmed: 15261482
doi: 10.1016/j.ceca.2004.02.011
Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nat. Med. 9, 669–676 (2003).
pubmed: 12778165
doi: 10.1038/nm0603-669
Ma, Y., Qu, Y. & Fei, Z. Vascular endothelial growth factor in cerebral ischemia. J. Neurosci. Res. 89, 969–978 (2011).
pubmed: 21469168
doi: 10.1002/jnr.22628
Kalaria, R. N. et al. Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia. Brain Res. Mol. Brain Res. 62, 101–105 (1998).
pubmed: 9795165
doi: 10.1016/S0169-328X(98)00190-9
Storkebaum, E. & Carmeliet, P. VEGF: A critical player in neurodegeneration. J. Clin. Invest. 113, 14–18 (2004).
pubmed: 14702101
pmcid: 300888
doi: 10.1172/JCI20682
Yang, S. P. et al. Co-accumulation of vascular endothelial growth factor with beta-amyloid in the brain of patients with Alzheimer’s disease. Neurobiol. Aging 25, 283–290 (2004).
pubmed: 15123332
doi: 10.1016/S0197-4580(03)00111-8
Mateo, I. et al. Low serum VEGF levels are associated with Alzheimer’s disease. Acta Neurol. Scand 116, 56–58 (2007).
pubmed: 17587256
doi: 10.1111/j.1600-0404.2006.00775.x
Tarkowski, E. et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiol. Aging 23, 237–243 (2002).
pubmed: 11804709
doi: 10.1016/S0197-4580(01)00285-8
He, D. et al. Vascular endothelial growth factor polymorphisms and risk of Alzheimer’s disease: A meta-analysis. Gene 518, 296–302 (2013).
pubmed: 23370341
doi: 10.1016/j.gene.2013.01.021
Kim, Y., Nam, Y. J. & Lee, C. Haplotype analysis of single nucleotide polymorphisms in VEGF gene for vascular dementia. Am. J. Med. Genet. B Neuropsychiatr. Gene 141B, 332–335 (2006).
doi: 10.1002/ajmg.b.30317
Takahashi, H. & Shibuya, M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin. Sci. (Lond) 109, 227–241 (2005).
pubmed: 16104843
doi: 10.1042/CS20040370
Patel, N. S. et al. Alzheimer’s beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2. J. Neurochem. 112, 66–76 (2010).
pubmed: 19818105
doi: 10.1111/j.1471-4159.2009.06426.x
Endres, M., Laufs, U., Liao, J. K. & Moskowitz, M. A. Targeting eNOS for stroke protection. Trends Neurosci. 27, 283–289 (2004).
pubmed: 15111011
doi: 10.1016/j.tins.2004.03.009
Li, S., Wang, W., Wang, C. & Tang, Y. Y. Possible involvement of NO/NOS signaling in hippocampal amyloid-β production induced by transient focal cerebral ischemia in aged rats. Neurosci. Lett. 470, 106–110 (2010).
pubmed: 20043977
doi: 10.1016/j.neulet.2009.12.064
Aliev, G. et al. Nitric oxide as an initiator of brain lesions during the development of Alzheimer disease. Neurotox Res. 16, 293–305 (2009).
pubmed: 19526276
doi: 10.1007/s12640-009-9066-5
de la Monte, S. M. et al. Nitric oxide synthase-3 overexpression causes apoptosis and impairs neuronal mitochondrial function: Relevance to Alzheimer’s-type neurodegeneration. Lab Invest. 83, 287–298 (2003).
pubmed: 12594242
doi: 10.1097/01.LAB.0000056995.07053.C0
Malinski, T. Nitric oxide and nitroxidative stress in Alzheimer’s disease. J. Alzheimers Dis. 11, 207–218 (2007).
pubmed: 17522445
doi: 10.3233/JAD-2007-11208
Alzheimer Research Forum, Drugs in Clinical Trials: AAB-001, http://www.alzforum.org/drg/drc/detail.asp?id=101 (2012).
Morris, C. M. et al. NOS3 gene rs1799983 polymorphism and incident dementia in elderly stroke survivors. Neurobiol. Aging 32(554), e1-6 (2011).
doi: 10.1016/j.neurobiolaging.2011.09.005
Nebel, R. A. et al. Understanding the impact of sex and geneder in Alzheimer´s disease: A call to action. Alzheimers Dement 14, 1171–1183 (2018).
pubmed: 29907423
pmcid: 6400070
doi: 10.1016/j.jalz.2018.04.008
Yang, X. et al. Polymorphisms in the vascular endothelial growth factor gene and the risk of diabetic retinopathy in Chinese patients with type 2 diabetes. Mol. Vis. 17, 3088–3096 (2011).
pubmed: 22162628
pmcid: 3233387
Oh, S. H. et al. Association between kinase insert domain-containing receptor gene polymorphism and haplotypes and ischemic stroke. J. Neurol. Sci. 308, 62–66 (2011).
pubmed: 21705026
doi: 10.1016/j.jns.2011.06.012
Zhang, W. et al. VEGF receptor-2 variants are associated with susceptibility to stroke and recurrence. Stroke 40, 2720–2726 (2009).
pubmed: 19520980
doi: 10.1161/STROKEAHA.109.554394
Han, I. B. et al. Association between kinase insert domain containing receptor gene polymorphisms and silent brain infarction: A Korean study. J. Neurol. Sci. 318, 85–89 (2012).
pubmed: 22520092
doi: 10.1016/j.jns.2012.03.020
Wittko-Schneider, I. M., Schneider, F. T. & Plate, K. H. Brain homeostasis: VEGF receptor 1 and 2-two unequal brothers in mind. Cell Mol. Life Sci. 70, 1705–1725 (2013).
pubmed: 23475067
pmcid: 3632714
doi: 10.1007/s00018-013-1279-3
Kuzuya, M. et al. VEGF protects against oxidized LDL toxicity to endothelial cells by an intracellular glutathione-dependent mechanism through the KDR receptor. Arterioscler. Thromb. Vasc. Biol. 21, 765–770 (2001).
pubmed: 11348872
doi: 10.1161/01.ATV.21.5.765
Wang, Y. et al. Polymorphisms of KDR gene are associated with coronary heart disease. J. Am. Coll. Cardiol. 50, 760–767 (2007).
pubmed: 17707181
doi: 10.1016/j.jacc.2007.04.074
Shibuya, M. Tyrosine kinase receptor Flt/VEGFR family: Its characterization related to angiogenesis and cancer. Genes Cancer 1, 1119–1123 (2010).
pubmed: 21779435
pmcid: 3092272
doi: 10.1177/1947601910392987
Qureshi, A. I. et al. Spontaneous intracerebral hemorrhage. N. Engl. J. Med. 344, 1450–1460 (2001).
pubmed: 11346811
doi: 10.1056/NEJM200105103441907
Ahmed-Jushuf, F. et al. Age-dependent expression of VEGFR2 in deep brain arteries in small vessel disease, CADASIL, and healthy brains. Neurobiol. Aging 42, 110–115 (2016).
pubmed: 27143427
doi: 10.1016/j.neurobiolaging.2016.03.002
Wang, Y. et al. VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. Brain 128, 52–63 (2005).
pubmed: 15509618
doi: 10.1093/brain/awh325
Stowe, A. M. et al. VEGF protein associates to neurons in remote regions following cortical infarct. J. Cereb Blood Flow Metab 27, 76–85 (2007).
pubmed: 16639424
doi: 10.1038/sj.jcbfm.9600320
Reitmeir, R. et al. Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain. Acta Neuropathol. 123, 273–284 (2012).
pubmed: 22109109
doi: 10.1007/s00401-011-0914-z
Wang, J. et al. Bone marrow mononuclear cell transplantation promotes therapeutic angiogenesis via upregulation of the VEGF-VEGFR2 signalling pathway in a rat model of vascular dementia. Behav. Brain Res. 265, 171–180 (2014).
pubmed: 24589546
pmcid: 4000455
doi: 10.1016/j.bbr.2014.02.033
Matsuda, H. Cerebral blood flow and metabolic abnormalities in Alzheimer’s disease. Ann. Nucl. Med. 15, 85–92 (2001).
pubmed: 11448080
doi: 10.1007/BF02988596
Religa, P. et al. VEGF significantly restores impaired memory behavior in Alzheimer’s mice by improvement of vascular survival. Sci. Rep. 3, 2053. https://doi.org/10.1038/srep02053 (2013).
doi: 10.1038/srep02053
pubmed: 23792494
pmcid: 3690383
Provias, J. & Jeynes, B. Reduction in vascular endothelial growth factor expression in the superior temporal, hippocampal, and brainstem regions in Alzheimer’s disease. Curr. Neurovasc. Res. 11, 202–209 (2014).
pubmed: 24845858
doi: 10.2174/1567202611666140520122316
Garcia, K. O. et al. Therapeutic effects of the transplantation of VEGF overexpressing bone marrow mesenchymal stem cells in the hippocampus of murine model of Alzheimer’s disease. Front. Aging Neurosci. 6, 30. https://doi.org/10.3389/fnagi.2014.00030 (2014).
doi: 10.3389/fnagi.2014.00030
pubmed: 24639647
pmcid: 3945612
Wang, P. et al. VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer’s disease. Biochem. Biophys. Res. Commun. 411, 620–626 (2011).
pubmed: 21771586
doi: 10.1016/j.bbrc.2011.07.003
Hohman, T. J., Bell, S. P. & Jefferson, A. L. Alzheimer’s Disease Neuroimaging Initiative. The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: Exploring interactions with biomarkers of Alzheimer disease. JAMA Neurol. 72, 520–529 (2014).
doi: 10.1001/jamaneurol.2014.4761
Blasko, I. et al. Measurement of thirteen biological markers in CSF of patients with Alzheimer’s disease and other dementias. Dement Geriatr. Cogn. Disord. 21, 9–15 (2006).
pubmed: 16244482
doi: 10.1159/000089137
Guo, L.-H., Alexopoulos, P. & Perneczky, R. Heart-type fatty acid binding protein and vascular endothelial growth factor: Cerebrospinal fluid biomarker candidates for Alzheimer’s disease. Eur. Arch. Psychiatry Clin. Neurosci. 263, 553–560 (2013).
pubmed: 23591828
doi: 10.1007/s00406-013-0405-4
Zhang, J. B. et al. Association of serum vascular endothelial growth factor levels and cerebral microbleeds in patients with Alzheimer’s disease. Eur. J. Neurol. 23, 1337–1342 (2016).
pubmed: 27128023
doi: 10.1111/ene.13030
Huang, L., Jia, J. & Liu, R. Decreased serum levels of the angiogenic factors VEGF and TGF-1 inAlzheimer’s disease and amnestic mild cognitive impairment. Neurosci. Lett. 550, 60–63 (2013).
pubmed: 23827227
doi: 10.1016/j.neulet.2013.06.031
Veldman, B. A. et al. The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide. J. Hypertens 20, 2023–2027 (2002).
pubmed: 12359981
doi: 10.1097/00004872-200210000-00022
Liu, S. et al. The nitric oxide synthase 3 G894T polymorphism associated with Alzheimer’s disease risk: A meta-analysis. Sci. Rep. 5, 13598. https://doi.org/10.1038/srep13598 (2015).
doi: 10.1038/srep13598
pubmed: 26337484
pmcid: 4559797
Patel, V. P. & Chu, C. T. Nuclear transport, oxidative stress, and neurodegeneration. Int. J. Clin. Exp. Pathol. 4, 215–229 (2011).
pubmed: 21487518
pmcid: 3071655
Austin, S. A., Santhanam, A. V., Hinton, D. J., Choi, D. S. & Katusic, Z. S. Endothelial nitric oxide deficiency promotes Alzheimer’s disease pathology. J. Neurochem. 127, 691–700 (2013).
pubmed: 23745722
pmcid: 3825764
doi: 10.1111/jnc.12334
Austin, S. A., Santhanam, A. V. & Katusic, Z. S. Endothelial nitric oxide modulates expression and processing of amyloid precursor protein. Circ. Res. 107, 1498–1502 (2010).
pubmed: 21127294
pmcid: 3064266
doi: 10.1161/CIRCRESAHA.110.233080
Chrysohoou, C. et al. Evidence for association between endothelial nitric oxide synthase gene polymorphism (G894T) and inflammatory markers: The ATTICA study. Am. Heart J. 148, 733–738 (2004).
pubmed: 15459608
doi: 10.1016/j.ahj.2004.04.022
Allan, C. L. & Ebmeier, K. P. The influence of ApoE4 on clinical progression of dementia: A meta-analysis. Int. J. Geriatr. Psychiatry 26, 520–526 (2011).
pubmed: 20845403
doi: 10.1002/gps.2559
Ruiz, A. et al. Exploratory analysis of seven Alzheimer’s disease genes: Disease progression. Neurobiol. Aging 34(4), 1310–1317 (2013).
doi: 10.1016/j.neurobiolaging.2012.08.014
McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 263–269 (2011).
pubmed: 21514250
pmcid: 3312024
doi: 10.1016/j.jalz.2011.03.005
Román, G. C. et al. Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43, 250–260 (1993).
pubmed: 8094895
doi: 10.1212/WNL.43.2.250
Folstein, M. F., Folstein, S. E. & McHugh, P. R. ‘“Mini-mental state”’. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189–198 (1975).
pubmed: 1202204
doi: 10.1016/0022-3956(75)90026-6
Cortes, F. et al. REAL-FR Group. Prognosis of Alzheimer’s disease today: A two-year prospective study in 686 patients from the REAL-FR Study. Alzheimers Dement 4, 22–29 (2008).
pubmed: 18631947
doi: 10.1016/j.jalz.2007.10.018
de Oliveira, F. F. et al. Lifetime risk factors for functional and cognitive outcomes in patients with Alzheimer’s disease. J. Alzheimers Dis. 65, 1283–1299 (2018).
pubmed: 30149448
doi: 10.3233/JAD-180303
Cummings, J. L. et al. The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 44, 2308–2314 (1994).
pubmed: 7991117
doi: 10.1212/WNL.44.12.2308