Is VEGF a Key Target of Cotinine and Other Potential Therapies Against Alzheimer Disease?

Author(s): Valentina Echeverria*, George E. Barreto, Marco Avila-Rodriguezc, Vadim V. Tarasov, Gjumrakch Aliev*

Journal Name: Current Alzheimer Research

Volume 14 , Issue 11 , 2017

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Abstract:

Background: The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions.

Conclusion: In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed.

Keywords: VEGF, Alzheimer disease, amyotrophic lateral sclerosis, cotinine, nicotinic receptors, depression, tobacco, angiogenesis, dementia, neurodegeneration.

[1]
Religa P, Cao R, Religa D, Xue Y, Bogdanovic N, Westaway D, et al. VEGF significantly restores impaired memory behavior in Alzheimer’s mice by improvement of vascular survival. Sci Rep 3: 2053. (2013).
[2]
Hohman TJ, Bell SP, Jefferson AL. Alzheimer’s Disease Neuroimaging I. The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease. JAMA Neurol 72(5): 520-9. (2015).
[3]
Luppi C, Fioravanti M, Bertolini B, Inguscio M, Grugnetti A, Guerriero F, et al. Growth factors decrease in subjects with mild to moderate Alzheimer’s disease (AD): potential correction with dehydroepiandrosterone-sulphate (DHEAS). Arch Gerontol Geriatr 49(1): 173-84. (2009).
[4]
Chapuis J, Tian J, Shi J, Bensemain F, Cottel D, Lendon C, et al. Association study of the vascular endothelial growth factor gene with the risk of developing Alzheimer’s disease. Neurobiol Aging 27(9): 1212-5. (2006).
[5]
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(3): 202-9. (2014).
[6]
Fournier NM, Duman RS. Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. Behav Brain Res 227(2): 440-9. (2012).
[7]
Viikki M, Anttila S, Kampman O, Illi A, Huuhka M, Setala-Soikkeli E, et al. Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression. Neurosci Lett 477(3): 105-8. (2010).
[8]
Isung J, Mobarrez F, Nordstrom P, Asberg M, Jokinen J. Low plasma vascular endothelial growth factor (VEGF) associated with completed suicide. World J Biol Psychiatry 13(6): 468-73. (2012).
[9]
Chio A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 41(2): 118-30. (2013).
[10]
Gordon PH. Amyotrophic lateral sclerosis: an update for 2013 clinical features, pathophysiology, management and therapeutic trials. Aging Dis 4(5): 295-310. (2013).
[11]
Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J. Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res 94(5): 664-70. (2004).
[12]
Nowacka MM, Obuchowicz E. Vascular endothelial growth factor (VEGF) and its role in the central nervous system: a new element in the neurotrophic hypothesis of antidepressant drug action. Neuropeptides 46(1): 1-10. (2012).
[13]
Patel NS, Mathura VS, Bachmeier C, Beaulieu-Abdelahad D, Laporte V, Weeks O, et al. Alzheimer’s beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2. J Neurochem 112(1): 66-76. (2010).
[14]
Xue Y, Chen F, Zhang D, Lim S, Cao Y. Tumor-derived VEGF modulates hematopoiesis. J Angiogenes Res 1: 9. (2009).
[15]
Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161(2): 851-8. (1989).
[16]
Krakora D, Mulcrone P, Meyer M, Lewis C, Bernau K, Gowing G, et al. Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model. Mol Ther 21(8): 1602-10. (2013).
[17]
Kirby ED, Kuwahara AA, Messer RL, Wyss-Coray T. Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF. Proc Natl Acad Sci USA 112(13): 4128-33. (2015).
[18]
Tillo M, Ruhrberg C, Mackenzie F. Emerging roles for semaphorins and VEGFs in synaptogenesis and synaptic plasticity. Cell Adh Migr 6(6): 541-6. (2012).
[19]
Licht T, Keshet E. Delineating multiple functions of VEGF-A in the adult brain. Cell Mol Life Sci 70(10): 1727-37. (2013).
[20]
Ma Y, Zechariah A, Qu Y, Hermann DM. Effects of vascular endothelial growth factor in ischemic stroke. J Neurosci Res 90(10): 1873-82. (2012).
[21]
Chen H, Xiong T, Qu Y, Zhao F, Ferriero D, Mu D. mTOR activates hypoxia-inducible factor-1alpha and inhibits neuronal apoptosis in the developing rat brain during the early phase after hypoxia-ischemia. Neurosci Lett 507(2): 118-23. (2012).
[22]
Kim BW, Choi M, Kim YS, Park H, Lee HR, Yun CO, et al. Vascular endothelial growth factor (VEGF) signaling regulates hippocampal neurons by elevation of intracellular calcium and activation of calcium/calmodulin protein kinase II and mammalian target of rapamycin. Cell Signal 20(4): 714-25. (2008).
[23]
Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res 66(8): 4249-55. (2006).
[24]
Ventriglia M, Zanardini R, Pedrini L, Placentino A, Nielsen MG, Gennarelli M, et al. VEGF serum levels in depressed patients during SSRI antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 33(1): 146-9. (2009).
[25]
Allaman I, Fiumelli H, Magistretti PJ, Martin JL. Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology (Berl) 216(1): 75-84. (2011).
[26]
Lee JS, Jang DJ, Lee N, Ko HG, Kim H, Kim YS, et al. Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors. J Neurosci 29(26): 8493-05. (2009).
[27]
Halmai Z, Dome P, Dobos J, Gonda X, Szekely A, Sasvari-Szekely M, et al. Peripheral vascular endothelial growth factor level is associated with antidepressant treatment response: results of a preliminary study. J Affect Disord 144(3): 269-73. (2013).
[28]
Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci USA 104(11): 4647-52. (2007).
[29]
Wu H, Lu D, Jiang H, Xiong Y, Qu C, Li B, et al. Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J Neurotrauma 25(2): 130-9. (2008).
[30]
Kiuchi T, Lee H, Mikami T. Regular exercise cures depression-like behavior via VEGF-Flk-1 signaling in chronically stressed mice. Neuroscience 207: 208-17. (2012).
[31]
Minelli A, Zanardini R, Abate M, Bortolomasi M, Gennarelli M, Bocchio-Chiavetto L. Vascular Endothelial Growth Factor (VEGF) serum concentration during electroconvulsive therapy (ECT) in treatment resistant depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 35(5): 1322-5. (2011).
[32]
Grizzell JA, Mullins M, Iarkov A, Rohani A, Charry LC, Echeverria V. Cotinine reduces depressive-like behavior and hippocampal vascular endothelial growth factor downregulation after forced swim stress in mice. Behav Neurosci 128(6): 713-21. (2014).
[33]
Grizzell JA, Iarkov A, Holmes R, Mori T, Echeverria V. Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice. Behav Brain Res 268: 55-65. (2014).
[34]
Moran VE. Cotinine: Beyond that expected, more than a biomarker of tobacco consumption. Front Pharmacol 3: 173. (2012).
[35]
Barreto GE, Iarkov A, Moran VE. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease. Front Aging Neurosci 6: 340. (2015).
[36]
Patel S, Grizzell JA, Holmes R, Zeitlin R, Solomon R, Sutton TL, et al. Cotinine halts the advance of Alzheimer’s disease-like pathology and associated depressive-like behavior in Tg6799 mice. Front Aging Neurosci 6: 162. (2014).
[37]
Grizzell JA, Echeverria V. New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine. Neurochem Res 40(10): 2032-46. (2015).
[38]
Rigau V, Morin M, Rousset MC, de Bock F, Lebrun A, Coubes P, et al. Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain 130(Pt 7): 1942-56. (2007).
[39]
Fidler IJ. The role of the organ microenvironment in brain metastasis. Semin Cancer Biol 21(2): 107-12. (2011).
[40]
Pucci S, Mazzarelli P, Missiroli F, Regine F, Ricci F. Neuroprotection: VEGF, IL-6, and clusterin: the dark side of the moon. Prog Brain Res 173: 555-73. (2008).
[41]
Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359(6398): 845-8. (1992).
[42]
Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A, et al. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 56(7): 1615-20. (1996).
[43]
Patt S, Danner S, Theallier-Janko A, Breier G, Hottenrott G, Plate KH, et al. Upregulation of vascular endothelial growth factor in severe chronic brain hypoxia of the rat. Neurosci Lett 252(3): 199-02. (1998).
[44]
Gora-Kupilas K, Josko J. The neuroprotective function of vascular endothelial growth factor (VEGF). Folia Neuropathol 43(1): 31-9. (2005).
[45]
Calvo CF, Fontaine RH, Soueid J, Tammela T, Makinen T, Alfaro-Cervello C, et al. Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis. Genes Dev 25(8): 831-44. (2011).
[46]
Herran E, Ruiz-Ortega JA, Aristieta A, Igartua M, Requejo C, Lafuente JV, et al. In vivo administration of VEGF- and GDNF-releasing biodegradable polymeric microspheres in a severe lesion model of Parkinson’s disease. Eur J Pharm Biopharm 85(3 Pt B): 1183-90. (2013).
[47]
Falk T, Yue X, Zhang S, McCourt AD, Yee BJ, Gonzalez RT, et al. Vascular endothelial growth factor-B is neuroprotective in an in vivo rat model of Parkinson’s disease. Neurosci Lett 496(1): 43-7. (2011).
[48]
Cui W, Li W, Han R, Mak S, Zhang H, Hu S, et al. PI3-K/Akt and ERK pathways activated by VEGF play opposite roles in MPP+-induced neuronal apoptosis. Neurochem Int 59(6): 945-53. (2011).
[49]
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 29(2): 230-4. (2009).
[50]
Yue X, Hariri DJ, Caballero B, Zhang S, Bartlett MJ, Kaut O, et al. Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson’s disease. Neuroscience 258: 385-400. (2014).
[51]
Herran E, Requejo C, Ruiz-Ortega JA, Aristieta A, Igartua M, Bengoetxea H, et al. Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson’s disease. Int J Nanomedicine 9: 2677-87. (2014).
[52]
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415): 59-62. (1993).
[53]
Strong M, Rosenfeld J. Amyotrophic lateral sclerosis: a review of current concepts. Amyotrophic lateral sclerosis and other motor neuron disorders: Official publication of the World Federation of Neurology. Research Group on Motor Neuron Diseases 4(3): 136-43. (2003).
[54]
Siddique T, Ajroud-Driss S. Familial amyotrophic lateral sclerosis, a historical perspective. Acta Myologica: Myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 30(2): 117-20 (2011).
[55]
Subramony SH, Ashizawa T, Langford L, McKenna R, Avvaru B, Siddique T, et al. Confirmation of the severe phenotypic effect of serine at codon 41 of the superoxide dismutase 1 gene. Muscle Nerve 44(4): 499-502. (2011).
[56]
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264(5166): 1772-5. (1994).
[57]
Gurney ME. Transgenic animal models of familial amyotrophic lateral sclerosis. J Neurol 244(2): S15-20. (1997).
[58]
Hall ED, Oostveen JA, Gurney ME. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23(3): 249-56. (1998).
[59]
Gurney ME. What transgenic mice tell us about neurodegenerative disease. BioEssays. News Rev Mol Cell Develop Biol 22(3): 297-304. (2000).
[60]
Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA 99(3): 1604-9. (2002).
[61]
Kalaria RN, Cohen DL, Premkumar DR, Nag S, LaManna JC, Lust WD. Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia. Brain Res Mol Brain Res 62(1): 101-5. (1998).
[62]
Tarkowski E, Issa R, Sjogren M, Wallin A, Blennow K, Tarkowski A, et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiol Aging 23(2): 237-43. (2002).
[63]
Mateo I, Llorca J, Infante J, Rodriguez-Rodriguez E, Fernandez-Viadero C, Pena N, et al. Low serum VEGF levels are associated with Alzheimer’s disease. Acta Neurol Scand 116(1): 56-8. (2007).
[64]
Mateo I, Llorca J, Infante J, Rodriguez-Rodriguez E, Sanchez-Quintana C, Sanchez-Juan P, et al. Case-control study of vascular endothelial growth factor (VEGF) genetic variability in Alzheimer’s disease. Neurosci Lett 401(1-2): 171-3. (2006).
[65]
Hermann MM, van Asten F, Muether PS, Smailhodzic D, Lichtner P, Hoyng CB, et al. Polymorphisms in vascular endothelial growth factor receptor 2 are associated with better response rates to ranibizumab treatment in age-related macular degeneration. Ophthalmology 121(4): 905-10. (2014).
[66]
Galecki P, Orzechowska A, Berent D, Talarowska M, Bobinska K, Galecka E, et al. Vascular endothelial growth factor receptor 2 gene (KDR) polymorphisms and expression levels in depressive disorder. J Affect Disord 147(1-3): 144-9. (2013).
[67]
Landgren S, Palmer MS, Skoog I, Minthon L, Wallin A, Andreasen N, et al. No association of VEGF polymorphims with Alzheimer’s disease. Neuromolecular Med 12(3): 224-8. (2010).
[68]
Tsai SJ, Hong CJ, Liou YJ, Chen TJ, Chen ML, Hou SJ, et al. Haplotype analysis of single nucleotide polymorphisms in the vascular endothelial growth factor (VEGFA) gene and antidepressant treatment response in major depressive disorder. Psychiatry Res 169(2): 113-7. (2009).
[69]
Del Bo R, Ghezzi S, Scarpini E, Bresolin N, Comi GP. VEGF genetic variability is associated with increased risk of developing Alzheimer’s disease. J Neurol Sci 283(1-2): 66-8. (2009).
[70]
Del Bo R, Ghezzi S, Scarlato M, Albani D, Galimberti D, Lucca U, et al. Role of VEGF gene variability in longevity: a lesson from the Italian population. Neurobiol Aging 29(12): 1917-22. (2008).
[71]
Del Bo R, Scarlato M, Ghezzi S, Martinelli Boneschi F, Fenoglio C, Galbiati S, et al. Vascular endothelial growth factor gene variability is associated with increased risk for AD. Ann Neurol 57(3): 373-80. (2005).
[72]
Burger S, Yafai Y, Bigl M, Wiedemann P, Schliebs R. Effect of VEGF and its receptor antagonist SU-5416, an inhibitor of angiogenesis, on processing of the beta-amyloid precursor protein in primary neuronal cells derived from brain tissue of Tg2576 mice. Int J Dev Neurosci 28(7): 597-604. (2010).
[73]
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 25(3): 283-90. (2004).
[74]
Herran E, Perez-Gonzalez R, Igartua M, Pedraz JL, Carro E, Hernandez RM. VEGF-releasing biodegradable nanospheres administered by craniotomy: a novel therapeutic approach in the APP/Ps1 mouse model of Alzheimer’s disease. J Control Release 170(1): 111-9. (2013).
[75]
Spuch C, Antequera D, Portero A, Orive G, Hernandez RM, Molina JA, et al. The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer’s disease. Biomaterials 31(21): 5608-18. (2010).
[76]
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 9(2): 59-65. (2006).
[77]
Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, et al. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18(10): 2803-12. (2003).
[78]
Udo H, Yoshida Y, Kino T, Ohnuki K, Mizunoya W, Mukuda T, et al. Enhanced adult neurogenesis and angiogenesis and altered affective behaviors in mice overexpressing vascular endothelial growth factor 120. J Neurosci 28(53): 14522-36. (2008).
[79]
McCloskey DP, Croll SD, Scharfman HE. Depression of synaptic transmission by vascular endothelial growth factor in adult rat hippocampus and evidence for increased efficacy after chronic seizures. J Neurosci 25(39): 8889-97. (2005).
[80]
Pati S, Orsi SA, Moore AN, Dash PK. Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory. Brain Res 1256: 85-91. (2009).
[81]
Craig-Schapiro R, Kuhn M, Xiong C, Pickering EH, Liu J, Misko TP, et al. Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer’s disease diagnosis and prognosis. PLoS One 6(4): e18850 (2011).
[82]
Blasko I, Lederer W, Oberbauer H, Walch T, Kemmler G, Hinterhuber H, et al. Measurement of thirteen biological markers in CSF of patients with Alzheimer’s disease and other dementias. Dement Geriatr Cogn Disord 21(1): 9-15. (2006).
[83]
Arnold SE, Xie SX, Leung YY, Wang LS, Kling MA, Han X, et al. Plasma biomarkers of depressive symptoms in older adults. Transl Psychiatry 2e65 (2012).
[84]
Laske C, Stellos K, Stransky E, Leyhe T, Gawaz M. Decreased plasma levels of granulocyte-colony stimulating factor (G-CSF) in patients with early Alzheimer’s disease. J Alzheimers Dis 17(1): 115-23. (2009).
[85]
Makanya AN, Styp-Rekowska B, Dimova I, Djonov V. Avian area vasculosa and CAM as rapid in vivo pro-angiogenic and antiangiogenic models. Methods Mol Biol 1214: 185-96. (2015).
[86]
Paris D, Townsend K, Quadros A, Humphrey J, Sun J, Brem S, et al. Inhibition of angiogenesis by Abeta peptides. Angiogenesis 7(1): 75-85. (2004).
[87]
Boscolo E, Folin M, Nico B, Grandi C, Mangieri D, Longo V, et al. Beta amyloid angiogenic activity in vitro and in vivo. Int J Mol Med 19(4): 581-7. (2007).
[88]
Viboolvorakul S, Patumraj S. Exercise training could improve age-related changes in cerebral blood flow and capillary vascularity through the upregulation of VEGF and eNOS. Biomed Res Int 2014: 230791 (2014).
[89]
Lazarovici P, Marcinkiewicz C, Lelkes PI. Cross talk between the cardiovascular and nervous systems: neurotrophic effects of vascular endothelial growth factor (VEGF) and angiogenic effects of nerve growth factor (NGF)-implications in drug development. Curr Pharm Des 12(21): 2609-22. (2006).
[90]
Wang P, Xie ZH, Guo YJ, Zhao CP, Jiang H, Song Y, et al. VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer’s disease. Biochem Biophys Res Commun 411(3): 620-6. (2011).


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 14
ISSUE: 11
Year: 2017
Page: [1155 - 1163]
Pages: 9
DOI: 10.2174/1567205014666170329113007
Price: $65

Article Metrics

PDF: 47
HTML: 8
EPUB: 1
PRC: 1