Adrenomedullin, a Novel Target for Neurodegenerative Diseases

  • Hilda Ferrero
  • Ignacio M. Larrayoz
  • Francisco J. Gil-Bea
  • Alfredo Martínez
  • María J. Ramírez


Neurodegenerative diseases represent a heterogeneous group of disorders whose common characteristic is the progressive degeneration of neuronal structure and function. Although much knowledge has been accumulated on the pathophysiology of neurodegenerative diseases over the years, more efforts are needed to understand the processes that underlie these diseases and hence to propose new treatments. Adrenomedullin (AM) is a multifunctional peptide involved in vasodilation, hormone secretion, antimicrobial defense, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins that interfere with microtubule dynamics. Furthermore, AM may intervene in neuronal dysfunction through other mechanisms such as immune and inflammatory response, apoptosis, or calcium dyshomeostasis. Alterations in AM expression have been described in neurodegenerative processes such as Alzheimer’s disease or vascular dementia. This review addresses the current state of knowledge on AM and its possible implication in neurodegenerative diseases.


Adrenomedullin Neurodegenerative diseases Cytoskeleton Alzheimer’s disease Vascular dementia 



H.F. is a recipient of a fellowship from Ministerio de Educación, Cultura y Deporte (FPU). I.M.L. is supported by a Miguel Servet contract (CP15/00198) from the “Instituto de Salud Carlos III-FEDER” (Fondo Europeo de Desarrollo Regional, a way to build Europe), and A.M. is supported by Fundación Rioja Salud (FRS).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T (1993) Adrenomedullin: a novel hypotensive peptide isolated from human Pheochromocytoma. Biochem Biophys Res Commun 192:553–560. PubMedCrossRefGoogle Scholar
  2. 2.
    Hinson JP, Kapas S, Smith DM (2000) Adrenomedullin, a multifunctional regulatory peptide1. Endocr Rev 21:138–167. PubMedGoogle Scholar
  3. 3.
    López J, Martínez A (2002) Cell and molecular biology of the multifunctional peptide, adrenomedullin. Int Rev Cytol 221:1–92PubMedCrossRefGoogle Scholar
  4. 4.
    Kohno M, Hanehira T, Kano H, et al (1996) Plasma adrenomedullin concentrations in essential hypertension. Hypertens (Dallas, Tex 1979) 27:102–7.Google Scholar
  5. 5.
    Cheung B, Leung R (1997) Elevated plasma levels of human adrenomedullin in cardiovascular, respiratory, hepatic and renal disorders. Clin Sci (Lond) 92:59–62CrossRefGoogle Scholar
  6. 6.
    Larráyoz IM, Martínez-Herrero S, García-Sanmartín J, Ochoa-Callejero L, Martínez A (2014) Adrenomedullin and tumour microenvironment. J Transl Med 12:339. PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Iesato Y, Yuda K, Chong KTY, Tan X, Murata T, Shindo T, Yanagi Y (2016) Adrenomedullin: a potential therapeutic target for retinochoroidal disease. Prog Retin Eye Res 52:112–129. PubMedCrossRefGoogle Scholar
  8. 8.
    Simon T-P, Martin L, Doemming S, Humbs A, Bruells C, Kopp R, Hartmann O, Struck J et al (2017) Plasma adrenomedullin in critically ill patients with sepsis after major surgery: a pilot study. J Crit Care 38:68–72.
  9. 9.
    Gillmann H-J, Meinders A, Larmann J, Sahlmann B, Schrimpf C, Aper T, Lichtinghagen R, Teebken OE et al (2017) Adrenomedullin is associated with surgical trauma and impaired renal function in vascular surgery patients. J Intensive Care Med 88506661668955:088506661668955.
  10. 10.
    Eguchi S, Hirata Y, Kano H, Sato K, Watanabe Y, Watanabe TX, Nakajima K, Sakakibara S et al (1994) Specific receptors for adrenomedullin in cultured rat vascular smooth muscle cells. FEBS Lett 340:226–230Google Scholar
  11. 11.
    Ishimitsu T, Kojima M, Kangawa K, Hino J, Matsuoka H, Kitamura K, Eto T, Matsuo H (1994) Genomic structure of human adrenomedullin gene. Biochem Biophys Res Commun 203:631–639. PubMedCrossRefGoogle Scholar
  12. 12.
    Sakata J, Shimokubo T, Kitamura K, Nishizono M, Iehiki Y, Kangawa K, Matsuo H, Eto T (1994) Distribution and characterization of immunoreactive rat adrenomedullin in tissue and plasma. FEBS Lett 352:105–108PubMedCrossRefGoogle Scholar
  13. 13.
    Kitamura K, Kangawa K, Ishiyama Y, Washimine H, Ichiki Y, Kawamoto M, Minamino N, Matsuo H et al (1994) Identification and hypotensive activity of proadrenomedullin N-terminal 20 peptide (PAMP). FEBS Lett 351:35–37Google Scholar
  14. 14.
    Martínez A, Bengoechea JA, Cuttitta F (2006) Molecular evolution of proadrenomedullin N-terminal 20 peptide (PAMP): evidence for gene co-option. Endocrinology 147:3457–3461. PubMedCrossRefGoogle Scholar
  15. 15.
    Martínez A, Zudaire E, Portal-Núñez S, Guédez L, Libutti SK, Stetler-Stevenson WG, Cuttitta F (2004) Proadrenomedullin NH2-terminal 20 peptide is a potent angiogenic factor, and its inhibition results in reduction of tumor growth. Cancer Res 64:6489–6494. PubMedCrossRefGoogle Scholar
  16. 16.
    Minamino N, Shoji H, Sugo S, Kangawa K, Matsuo H (1995) Adrenocortical steroids, thyroid hormones and retinoic acid augment the production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun 211:686–693. PubMedCrossRefGoogle Scholar
  17. 17.
    Sugo S, Minamino N, Shoji H, Kangawa K, Kitamura K, Eto T, Matsuo H (1995) Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun 207:25–32. PubMedCrossRefGoogle Scholar
  18. 18.
    Sugo S, Minamino N, Shoji H, Kangawa K, Matsuo H (1995) Effects of vasoactive substances and cAMP related compounds on adrenomedullin production in cultured vascular smooth muscle cells. FEBS Lett 369:311–314PubMedCrossRefGoogle Scholar
  19. 19.
    Garayoa M, Martínez A, Lee S, Pío R, An WG, Neckers L, Trepel J, Montuenga LM et al (2000) Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis. Mol Endocrinol 14:848–862.
  20. 20.
    Ichiki Y, Kitamura K, Kangawa K, Kawamoto M, Matsuo H, Eto T (1994) Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma. FEBS Lett 338:6–10PubMedCrossRefGoogle Scholar
  21. 21.
    Ueta Y, Kitamura K, Isse T, Shibuya I, Kabashima N, Yamamoto S, Kangawa K, Matsuo H et al (1995) Adrenomedullin-immunoreactive neurons in the paraventricular and supraoptic nuclei of the rat. Neurosci Lett 202:37–40Google Scholar
  22. 22.
    Washimine H, Asada Y, Kitamura K, Ichiki Y, Hara S, Yamamoto Y, Kangawa K, Sumiyoshi A et al (1995) Immunohistochemical identification of adrenomedullin in human, rat, and porcine tissue. Histochem Cell Biol 103(4):251–254Google Scholar
  23. 23.
    Satoh F, Takahashi K, Murakami O, Totsune K, Sone M, Ohneda M, Sasano H, Mouri T (1996) Immunocytochemical localization of adrenomedullin-like immunoreactivity in the human hypothalamus and the adrenal gland. Neurosci Lett 203:207–210PubMedCrossRefGoogle Scholar
  24. 24.
    Montuenga LM, Martínez A, Miller MJ, Unsworth EJ, Cuttitta F (1997) Expression of adrenomedullin and its receptor during embryogenesis suggests autocrine or paracrine modes of action. Endocrinology 138:440–451. PubMedCrossRefGoogle Scholar
  25. 25.
    Serrano J, Uttenthal LO, Martínez A et al (2000) Distribution of adrenomedullin-like immunoreactivity in the rat central nervous system by light and electron microscopy. Brain Res 853:245–268PubMedCrossRefGoogle Scholar
  26. 26.
    Kitamura K, Kangawa K, Eto T (2002) Adrenomedullin and PAMP: discovery, structures, and cardiovascular functions. Microsc Res Tech 57:3–13. PubMedCrossRefGoogle Scholar
  27. 27.
    Kato J, Kitamura K (2015) Bench-to-bedside pharmacology of adrenomedullin. Eur J Pharmacol 764:140–148. PubMedCrossRefGoogle Scholar
  28. 28.
    Eto T, Kitamura K, Kato J (1999) Biological and clinical roles of adrenomedullin in circulation control and cardiovascular diseases. Clin Exp Pharmacol Physiol 26:371–380PubMedCrossRefGoogle Scholar
  29. 29.
    Tsuruda T, Kato J, Kitamura K, et al (1998) Adrenomedullin: a possible autocrine or paracrine inhibitor of hypertrophy of cardiomyocytes. Hypertens (Dallas, Tex 1979) 31:505–10.Google Scholar
  30. 30.
    Takahashi K, Satoh F, Hara E, Sone M, Murakami O, Kayama T, Yoshimoto T, Shibahara S (1997) Production and secretion of adrenomedullin from glial cell tumors and its effects on cAMP production. Peptides 18:1117–1124PubMedCrossRefGoogle Scholar
  31. 31.
    Tixier E, Leconte C, Touzani O, Roussel S, Petit E, Bernaudin M (2008) Adrenomedullin protects neurons against oxygen glucose deprivation stress in an autocrine and paracrine manner. J Neurochem 106:1388–1403. PubMedCrossRefGoogle Scholar
  32. 32.
    Sugo S, Minamino N, Kangawa K, Miyamoto K, Kitamura K, Sakata J, Eto T, Matsuo H (1994) Endothelial cells actively synthesize and secrete adrenomedullin. Biochem Biophys Res Commun 201:1160–1166. PubMedCrossRefGoogle Scholar
  33. 33.
    Pı́o R, Martı́nez A, Unsworth EJ, Kowalak JA, Bengoechea JA, Zipfel PF, Elsasser TH, Cuttitta F (2001) Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem 276:12292–12300. PubMedCrossRefGoogle Scholar
  34. 34.
    Dupuis J, Caron A, Ruël N (2005) Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin. Clin Sci (Lond) 109:97–102. CrossRefGoogle Scholar
  35. 35.
    Martínez A, Oh H-R, Unsworth EJ et al (2004) Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator. Biochem J 383:413–418. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Juaneda C, Dumont Y, Chabot JG, Fournier A, Quirion R (2003) Adrenomedullin receptor binding sites in rat brain and peripheral tissues. Eur J Pharmacol 474:165–174PubMedCrossRefGoogle Scholar
  37. 37.
    Muff R, Born W, Fischer JA (2001) Adrenomedullin and related peptides: receptors and accessory proteins. Peptides 22:1765–1772PubMedCrossRefGoogle Scholar
  38. 38.
    Hay DL, Smith DM (2001) Adrenomedullin receptors: molecular identity and function. Peptides 22:1753–1763PubMedCrossRefGoogle Scholar
  39. 39.
    Poyner DR (1997) Molecular pharmacology of receptors for calcitonin-gene-related peptide, amylin and adrenomedullin. Biochem Soc Trans 25:1032–1036PubMedCrossRefGoogle Scholar
  40. 40.
    Foord SM, McLatchie LM, Fraser NJ et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339. PubMedCrossRefGoogle Scholar
  41. 41.
    Qi T, Christopoulos G, Bailey RJ, Christopoulos A, Sexton PM, Hay DL (2008) Identification of N-terminal receptor activity-modifying protein residues important for calcitonin gene-related peptide, adrenomedullin, and amylin receptor function. Mol Pharmacol 74:1059–1071. PubMedCrossRefGoogle Scholar
  42. 42.
    Hirata Y, Hayakawa H, Suzuki Y, et al (1995) Mechanisms of adrenomedullin-induced vasodilation in the rat kidney. Hypertens (Dallas, Tex 1979) 25:790–5.Google Scholar
  43. 43.
    Nishimatsu H, Suzuki E, Nagata D, Moriyama N, Satonaka H, Walsh K, Sata M, Kangawa K et al (2001) Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3-kinase/Akt-dependent pathway in rat aorta. Circ Res 89:63–70Google Scholar
  44. 44.
    Fritz-Six KL, Dunworth WP, Li M, Caron KM (2008) Adrenomedullin signaling is necessary for murine lymphatic vascular development. J Clin Invest 118:40–50. PubMedCrossRefGoogle Scholar
  45. 45.
    Yurugi-Kobayashi T, Itoh H, Schroeder T et al (2006) Adrenomedullin/cyclic AMP pathway induces Notch activation and differentiation of arterial endothelial cells from vascular progenitors. Arterioscler Thromb Vasc Biol 26:1977–1984. PubMedCrossRefGoogle Scholar
  46. 46.
    Fletcher DA, Mullins RD (2010) Cell mechanics and the cytoskeleton. Nature 463:485–492. PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Craig AM, Banker G (1994) Neuronal polarity. Annu Rev Neurosci 17:267–310. PubMedCrossRefGoogle Scholar
  48. 48.
    Spudich JA, Huxley HE, Finch JT (1972) Regulation of skeletal muscle contraction. II Structural studies of the interaction of the tropomyosin-troponin complex with actin J Mol Biol 72:619–632PubMedGoogle Scholar
  49. 49.
    Luo L (2002) Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu Rev Cell Dev Biol 18:601–635. PubMedCrossRefGoogle Scholar
  50. 50.
    Watanabe K, Al-Bassam S, Miyazaki Y et al (2012) Networks of polarized actin filaments in the axon initial segment provide a mechanism for sorting axonal and dendritic proteins. Cell Rep 2:1546–1553. PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Cairns NJ, Lee VM-Y, Trojanowski JQ (2004) The cytoskeleton in neurodegenerative diseases. J Pathol 204:438–449. PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Eira J, Silva CS, Sousa MM, Liz MA (2016) The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders. Prog Neurobiol 141:61–82. PubMedCrossRefGoogle Scholar
  53. 53.
    Zhu Q, Couillard-Després S, Julien J-P (1997) Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Exp Neurol 148:299–316. PubMedCrossRefGoogle Scholar
  54. 54.
    Prokop A (2013) The intricate relationship between microtubules and their associated motor proteins during axon growth and maintenance. Neural Dev 8:17. PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Conde C, Cáceres A (2009) Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci 10:319–332. PubMedCrossRefGoogle Scholar
  56. 56.
    Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, Grigoriev I, Camera P, Spangler SA et al (2009) Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron 61:85–100.
  57. 57.
    Downing KH, Nogales E (1998) Tubulin and microtubule structure. Curr Opin Cell Biol 10:16–22PubMedCrossRefGoogle Scholar
  58. 58.
    Erickson HP, O’Brien ET (1992) Microtubule dynamic instability and GTP hydrolysis. Annu Rev Biophys Biomol Struct 21:145–166. PubMedCrossRefGoogle Scholar
  59. 59.
    Hyman AA, Salser S, Drechsel DN, Unwin N, Mitchison TJ (1992) Role of GTP hydrolysis in microtubule dynamics: information from a slowly hydrolyzable analogue, GMPCPP. Mol Biol Cell 3:1155–1167PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Mitchison T, Kirschner M (1984) Dynamic instability of microtubule growth. Nature 312:237–242PubMedCrossRefGoogle Scholar
  61. 61.
    Walker RA, O’Brien ET, Pryer NK et al (1988) Dynamic instability of individual microtubules analyzed by video light microscopy: rate constants and transition frequencies. J Cell Biol 107:1437–1448PubMedCrossRefGoogle Scholar
  62. 62.
    Desai A, Mitchison TJ (1997) Microtubule polymerization dynamics. Annu Rev Cell Dev Biol 13:83–117. PubMedCrossRefGoogle Scholar
  63. 63.
    Soppina V, Herbstman JF, Skiniotis G, Verhey KJ (2012) Luminal localization of α-tubulin K40 acetylation by cryo-EM analysis of fab-labeled microtubules. PLoS One 7:e48204. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Li L, Yang X-J (2015) Tubulin acetylation: responsible enzymes, biological functions and human diseases. Cell Mol Life Sci 72:4237–4255. PubMedCrossRefGoogle Scholar
  65. 65.
    Lacroix B, van Dijk J, Gold ND, Guizetti J, Aldrian-Herrada G, Rogowski K, Gerlich DW, Janke C (2010) Tubulin polyglutamylation stimulates spastin-mediated microtubule severing. J Cell Biol 189:945–954. PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Hirokawa N, Niwa S, Tanaka Y (2010) Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron 68:610–638. PubMedCrossRefGoogle Scholar
  67. 67.
    Cai D, McEwen DP, Martens JR et al (2009) Single molecule imaging reveals differences in microtubule track selection between kinesin motors. PLoS Biol 7:e1000216PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Takemura R, Okabe S, Umeyama T et al (1992) Increased microtubule stability and alpha tubulin acetylation in cells transfected with microtubule-associated proteins MAP1B, MAP2 or tau. J Cell Sci 103(Pt 4):953–964PubMedGoogle Scholar
  69. 69.
    Larráyoz IM, Martínez-herrero S, Ochoa-callejero L, et al (2013) Is the cytoskeleton an intracellular receptor for adrenomedullin and PAMP? 429–443.
  70. 70.
    Sackett DL, Ozbun L, Zudaire E, Wessner L, Chirgwin JM, Cuttitta F, Martínez A (2008) Intracellular proadrenomedullin-derived peptides decorate the microtubules and contribute to cytoskeleton function. Endocrinology 149:2888–2898. PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Szebenyi G, Bollati F, Bisbal M, Sheridan S, Faas L, Wray R, Haferkamp S, Nguyen S et al (2005) Activity-driven dendritic remodeling requires microtubule-associated protein 1A. Curr Biol 15:1820–1826.
  72. 72.
    Liu Y, Lee JW, Ackerman SL (2015) Mutations in the microtubule-associated protein 1A (Map1a) gene cause Purkinje cell degeneration. J Neurosci 35:4587–4598. PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Kortazar D, Fanarraga ML, Carranza G, Bellido J, Villegas JC, Avila J, Zabala JC (2007) Role of cofactors B (TBCB) and E (TBCE) in tubulin heterodimer dissociation. Exp Cell Res 313:425–436. PubMedCrossRefGoogle Scholar
  74. 74.
    Hoffman PN, Lopata MA, Watson DF, Luduena RF (1992) Axonal transport of class II and III beta-tubulin: evidence that the slow component wave represents the movement of only a small fraction of the tubulin in mature motor axons. 119:595–604.Google Scholar
  75. 75.
    Li C, Zheng Y, Qin W, Tao R, Pan Y, Xu Y, Li X, Gu N et al (2006) A family-based association study of kinesin heavy chain member 2 gene (KIF2) and schizophrenia. Neurosci Lett 407:151–155.
  76. 76.
    Larráyoz IM, Martínez A (2012) Proadrenomedullin N-terminal 20 peptide increases kinesin’s velocity both in vitro and in vivo. Endocrinology 153:1734–1742. PubMedCrossRefGoogle Scholar
  77. 77.
    Fernández AP, Serrano J, Tessarollo L et al (2008) Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions. Proc Natl Acad Sci U S A 105:12581–12586. PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Vergaño-Vera E, Fernández AP, Hurtado-Chong A, Vicario-Abejón C, Martínez A (2010) Lack of adrenomedullin affects growth and differentiation of adult neural stem/progenitor cells. Cell Tissue Res 340:1–11. PubMedCrossRefGoogle Scholar
  79. 79.
    Larrayoz IM, Ochoa-Callejero L, García-Sanmartín J et al (2012) Role of adrenomedullin in the growth and differentiation of stem and progenitor cells. Int Rev Cell Mol Biol:175–234Google Scholar
  80. 80.
    Niu P, Shindo T, Iwata H, Iimuro S, Takeda N, Zhang Y, Ebihara A, Suematsu Y et al (2004) Protective effects of endogenous adrenomedullin on cardiac hypertrophy, fibrosis, and renal damage. Circulation 109:1789–1794.
  81. 81.
    Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640–651. PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, Read S, Satyamurthy N et al (2002) Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 10:24–35Google Scholar
  83. 83.
    Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608. PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science (80- ) 298:789–791.
  85. 85.
    Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2:a006270. PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204. PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344. PubMedCrossRefGoogle Scholar
  88. 88.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science (80- ) 297:353–356.
  89. 89.
    Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2:a006338–a006338. PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 45:358–368PubMedCrossRefGoogle Scholar
  91. 91.
    Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P et al (2011) Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J Neurosci 31:700–711.
  92. 92.
    Iqbal K, Liu F, Gong C-X (2015) Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12:15–27. PubMedCrossRefGoogle Scholar
  93. 93.
    Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12:609–622. PubMedCrossRefGoogle Scholar
  94. 94.
    Medina M, Hernández F, Avila J (2016) New features about tau function and dysfunction. Biomol Ther 6:21. Google Scholar
  95. 95.
    Shimura H, Schwartz D, Gygi SP, Kosik KS (2004) CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem 279:4869–4876. PubMedCrossRefGoogle Scholar
  96. 96.
    Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K (1997) Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci U S A 94:298–303PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Titani K, Ihara Y (1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau. J Biol Chem 270:823–829PubMedCrossRefGoogle Scholar
  98. 98.
    Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA et al (2010) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067–1081.
  99. 99.
    Lee H, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A et al (2005) Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med 11:164–169.
  100. 100.
    Gómez-Ramos A, Díaz-Hernández M, Cuadros R, Hernández F, Avila J (2006) Extracellular tau is toxic to neuronal cells. FEBS Lett 580:4842–4850. PubMedCrossRefGoogle Scholar
  101. 101.
    Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE (2015) Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med 22:46–53. PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1:213–216PubMedCrossRefGoogle Scholar
  103. 103.
    de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N et al (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697.
  104. 104.
    Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7:e31302. PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Fernandez AP, Masa JS, Guedan MA et al (2016) Adrenomedullin expression in Alzheimer’s brain. Curr Alzheimer Res 13:428–438PubMedCrossRefGoogle Scholar
  106. 106.
    Ferrero H, Larrayoz IM, Martisova E, Solas M, Howlett DR, Francis PT, Gil-Bea FJ, Martínez A et al (2017) Increased levels of brain adrenomedullin in the neuropathology of Alzheimer’s disease. Mol Neurobiol.
  107. 107.
    Agostinho P, Cunha RA, Oliveira C (2010) Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des 16:2766–2778PubMedCrossRefGoogle Scholar
  108. 108.
    Jahnke GD, Brunssen S, Maier WE, Harry GJ (2001) Neurotoxicant-induced elevation of adrenomedullin expression in hippocampus and glia cultures. J Neurosci Res 66:464–474. PubMedCrossRefGoogle Scholar
  109. 109.
    Consonni A, Morara S, Codazzi F, Grohovaz F, Zacchetti D (2011) Inhibition of lipopolysaccharide-induced microglia activation by calcitonin gene related peptide and adrenomedullin. Mol Cell Neurosci 48:151–160. PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Wong LYF, Cheung BMY, Li Y-Y, Tang F (2005) Adrenomedullin is both proinflammatory and antiinflammatory: its effects on gene expression and secretion of cytokines and macrophage migration inhibitory factor in NR8383 macrophage cell line. Endocrinology 146:1321–1327. PubMedCrossRefGoogle Scholar
  111. 111.
    Verweij N, Mahmud H, Leach IM, de Boer RA, Brouwers FP, Yu H, Asselbergs FW, Struck J et al (2013) Genome-wide association study on plasma levels of midregional-proadrenomedullin and C-terminal-pro-endothelin-1. Hypertension 61:602–608.
  112. 112.
    Buerger K, Uspenskaya O, Hartmann O, Hansson O, Minthon L, Blennow K, Moeller HJ, Teipel SJ et al (2011) Prediction of Alzheimer’s disease using midregional proadrenomedullin and midregional proatrial natriuretic peptide. J Clin Psychiatry 72:556–563.
  113. 113.
    Ewers M, Mielke MM, Hampel H (2010) Blood-based biomarkers of microvascular pathology in Alzheimer’s disease. Exp Gerontol 45:75–79. PubMedCrossRefGoogle Scholar
  114. 114.
    Henriksen K, O’Bryant SE, Hampel H et al (2014) The future of blood-based biomarkers for Alzheimer’s disease. Alzheimers Dement 10:115–131. PubMedCrossRefGoogle Scholar
  115. 115.
    Zhang H, Tang B, Yin C-G, Chen Y, Meng QL, Jiang L, Wang WP, Niu GZ (2014) Plasma adrenomedullin levels are associated with long-term outcomes of acute ischemic stroke. Peptides 52:44–48. PubMedCrossRefGoogle Scholar
  116. 116.
    O’Brien JT, Thomas A (2015) Vascular dementia. Lancet 386:1698–1706. PubMedCrossRefGoogle Scholar
  117. 117.
    Román GC (2004) Facts, myths, and controversies in vascular dementia. J Neurol Sci 226:49–52. PubMedCrossRefGoogle Scholar
  118. 118.
    Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG (2009) CADASIL. Lancet Neurol 8:643–653. PubMedCrossRefGoogle Scholar
  119. 119.
    Leblanc GG, Meschia JF, Stuss DT, Hachinski V (2006) Genetics of vascular cognitive impairment: the opportunity and the challenges. Stroke 37:248–255. PubMedCrossRefGoogle Scholar
  120. 120.
    Deramecourt V, Slade JY, Oakley AE, Perry RH, Ince PG, Maurage CA, Kalaria RN (2012) Staging and natural history of cerebrovascular pathology in dementia. Neurology 78:1043–1050. PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Ihara M, Polvikoski TM, Hall R, Slade JY, Perry RH, Oakley AE, Englund E, O’Brien JT et al (2010) Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies. Acta Neuropathol 119:579–589.
  122. 122.
    Englund E (1998) Neuropathology of white matter changes in Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord 9(Suppl 1):6–12PubMedCrossRefGoogle Scholar
  123. 123.
    Vinters HV, Ellis WG, Zarow C, Zaias BW, Jagust WJ, Mack WJ, Chui HC (2000) Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 59:931–945PubMedCrossRefGoogle Scholar
  124. 124.
    Iemolo F, Duro G, Rizzo C, Castiglia L, Hachinski V, Caruso C (2009) Pathophysiology of vascular dementia. Immun Ageing 6:13. PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Bronge L, Wahlund LO (2000) White matter lesions in dementia: an MRI study on blood-brain barrier dysfunction. Dement Geriatr Cogn Disord 11:263–267. PubMedCrossRefGoogle Scholar
  126. 126.
    Farrall AJ, Wardlaw JM (2009) Blood–brain barrier: ageing and microvascular disease—systematic review and meta-analysis. Neurobiol Aging 30:337–352. PubMedCrossRefGoogle Scholar
  127. 127.
    Kis B, Deli MA, Kobayashi H, Ábrahám CS, Yanagita T, Kaiya H, Isse T, Nishi R et al (2001) Adrenomedullin regulates blood-brain barrier functions in vitro. Neuroreport 12:4139–4142Google Scholar
  128. 128.
    Kis B, Abrahám CS, Deli MA et al (2001) Adrenomedullin in the cerebral circulation. Peptides 22:1825–1834PubMedCrossRefGoogle Scholar
  129. 129.
    Bełtowski J, Jamroz A (2004) Adrenomedullin—what do we know 10 years since its discovery? Pol J Pharmacol 56:5–27PubMedGoogle Scholar
  130. 130.
    Xia C-F, Smith RS, Shen B, Yang ZR, Borlongan CV, Chao L, Chao J (2006) Postischemic brain injury is exacerbated in mice lacking the kinin B2 receptor. Hypertension 47:752–761. PubMedCrossRefGoogle Scholar
  131. 131.
    Watanabe K, Takayasu M, Takagi T, Suzuki Y, Noda A, Hara M, Yoshia J (2001) Adrenomedullin reduces ischemic brain injury after transient middle cerebral artery occlusion in rats. Acta Neurochir 143:1157–1161. PubMedCrossRefGoogle Scholar
  132. 132.
    Xia C-F, Yin H, Borlongan CV, Chao J, Chao L (2004) Adrenomedullin gene delivery protects against cerebral ischemic injury by promoting astrocyte migration and survival. Hum Gene Ther 15:1243–1254. PubMedCrossRefGoogle Scholar
  133. 133.
    Dogan A, Suzuki Y, Koketsu N, Osuka K, Saito K, Takayasu M, Shibuya M, Yoshida J (1997) Intravenous infusion of adrenomedullin and increase in regional cerebral blood flow and prevention of ischemic brain injury after middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 17:19–25. PubMedCrossRefGoogle Scholar
  134. 134.
    Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31:424–428. PubMedCrossRefGoogle Scholar
  135. 135.
    Maki T, Ihara M, Fujita Y, Nambu T, Miyashita K, Yamada M, Washida K, Nishio K et al (2011) Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice. Stroke 42:1122–1128.
  136. 136.
    Liverani E, Paul C (2013) Glucocorticoids alter adrenomedullin receptor expression and secretion in endothelial-like cells and astrocytes. Int J Biochem Cell Biol 45:2715–2723. PubMedCrossRefGoogle Scholar
  137. 137.
    Serrano J, Alonso D, Fernández AP, Encinas JM, López JC, Castro-Blanco S, Fernández-Vizarra P, Richart A et al (2002) Adrenomedullin in the central nervous system. Microsc Res Tech 57:76–90.
  138. 138.
    Miyamoto N, Tanaka R, Shimosawa T, Yatomi Y, Fujita T, Hattori N, Urabe T (2009) Protein kinase A-dependent suppression of reactive oxygen species in transient focal ischemia in adrenomedullin-deficient mice. J Cereb Blood Flow Metab 29:1769–1779. PubMedCrossRefGoogle Scholar
  139. 139.
    Fernandez AP, Serrano J, Amorim MA et al (2011) Adrenomedullin and nitric oxide: implications for the etiology and treatment of primary brain tumors. CNS Neurol Disord Drug Targets 10:820–833PubMedCrossRefGoogle Scholar
  140. 140.
    Kis B, Chen L, Ueta Y, Busija DW (2006) Autocrine peptide mediators of cerebral endothelial cells and their role in the regulation of blood-brain barrier. Peptides 27:211–222. PubMedCrossRefGoogle Scholar
  141. 141.
    Holm H, Nägga K, Nilsson ED, Ricci F, Melander O, Hansson O, Bachus E, Magnusson M et al (2017) Biomarkers of microvascular endothelial dysfunction predict incident dementia: a population-based prospective study. J Intern Med 282:94–101.
  142. 142.
    Dohgu S, Sumi N, Nishioku T, Takata F, Watanabe T, Naito M, Shuto H, Yamauchi A et al (2010) Cyclosporin a induces hyperpermeability of the blood–brain barrier by inhibiting autocrine adrenomedullin-mediated up-regulation of endothelial barrier function. Eur J Pharmacol 644:5–9.
  143. 143.
    Kuriyama N, Ihara M, Mizuno T, Ozaki E, Matsui D, Watanabe I, Koyama T, Kondo M et al (2017) Association between mid-regional proadrenomedullin levels and progression of deep white matter lesions in the brain accompanying cognitive decline. J Alzheimers Dis 56:1253–1262.
  144. 144.
    Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066. PubMedCrossRefGoogle Scholar
  145. 145.
    Shaw LM, Korecka M, Clark CM, Lee VMY, Trojanowski JQ (2007) Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nat Rev Drug Discov 6:295–303. PubMedCrossRefGoogle Scholar
  146. 146.
    Dawson TM, Dawson VL (2010) The role of parkin in familial and sporadic Parkinson’s disease. Mov Disord 25:S32–S39. PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Yang F, Jiang Q, Zhao J, Ren Y, Sutton MD, Feng J (2005) Parkin stabilizes microtubules through strong binding mediated by three independent domains. J Biol Chem 280:17154–17162. PubMedCrossRefGoogle Scholar
  148. 148.
    Ross CA, Tabrizi SJ (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10:83–98. PubMedCrossRefGoogle Scholar
  149. 149.
    Fernández-Nogales M, Santos-Galindo M, Hernández IH, Cabrera JR, Lucas JJ (2016) Faulty splicing and cytoskeleton abnormalities in Huntington’s disease. Brain Pathol 26:772–778. PubMedCrossRefGoogle Scholar
  150. 150.
    Rohrer JD (2012) Structural brain imaging in frontotemporal dementia. Biochim Biophys Acta - Mol Basis Dis 1822:325–332. CrossRefGoogle Scholar
  151. 151.
    Wszolek ZK, Tsuboi Y, Ghetti B, Pickering-Brown S, Baba Y, Cheshire WP (2006) Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Orphanet J Rare Dis 1:30. PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Martínez-Herrero S, Larrayoz IM, Ochoa-Callejero L, Fernández LJ, Allueva A, Ochoa I, Martínez A (2016) Prevention of bone loss in a model of postmenopausal osteoporosis through adrenomedullin inhibition. Front Physiol 7:280. PubMedPubMedCentralGoogle Scholar
  153. 153.
    Chung W-S, Barres BA (2012) The role of glial cells in synapse elimination. Curr Opin Neurobiol 22:438–445. PubMedCrossRefGoogle Scholar
  154. 154.
    Lee H-J, Suk J-E, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E et al (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–9272.
  155. 155.
    Barcia C, Ros CM, Annese V, Gómez A, Ros-Bernal F, Aguado-Llera D, Martínez-Pagán ME, de Pablos V et al (2011) IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis 2:e142.
  156. 156.
    Takahashi K, Nakayama M, Totsune K, Murakami O, Sone M, Kitamuro T, Yoshinoya A, Shibahara S (2001) Increased secretion of adrenomedullin from cultured human astrocytes by cytokines. J Neurochem 74:99–103. CrossRefGoogle Scholar
  157. 157.
    Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934. PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Pedreño M, Morell M, Robledo G, Souza-Moreira L, Forte-Lago I, Caro M, O’Valle F, Ganea D et al (2014) Adrenomedullin protects from experimental autoimmune encephalomyelitis at multiple levels. Brain Behav Immun 37:152–163.
  159. 159.
    Elsasser TH, Kahl S (2002) Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc Res Tech 57:120–129. PubMedCrossRefGoogle Scholar
  160. 160.
    Zeng X, Lin MY, Wang D, Zhang Y, Hong Y (2014) Involvement of adrenomedullin in spinal glial activation following chronic administration of morphine in rats. Eur J Pain 18:1323–1332. PubMedCrossRefGoogle Scholar
  161. 161.
    Mocco J, Mack WJ, Ducruet AF, Sosunov SA, Sughrue ME, Hassid BG, Nair MN, Laufer I et al (2006) Complement component C3 mediates inflammatory injury following focal cerebral ischemia. Circ Res 99:209–217.
  162. 162.
    Cheyuo C, Yang W-L, Wang P (2012) The critical role of adrenomedullin and its binding protein, AMBP-1, in neuroprotection. Biol Chem 393:429–439. PubMedCrossRefGoogle Scholar
  163. 163.
    Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354–365. PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Chen W, Zhang X, Huang W (2016) Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 13:3391–3396. PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Sardi C, Zambusi L, Finardi A, Ruffini F, Tolun AA, Dickerson IM, Righi M, Zacchetti D et al (2014) Involvement of calcitonin gene-related peptide and receptor component protein in experimental autoimmune encephalomyelitis. J Neuroimmunol 271:18–29.
  166. 166.
    Gonzalez-Rey E, Chorny A, O’Valle F, Delgado M (2007) Adrenomedullin protects from experimental arthritis by down-regulating inflammation and Th1 response and inducing regulatory T cells. Am J Pathol 170:263–271. PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Miksa M, Wu R, Cui X, Dong W, Das P, Simms HH, Ravikumar TS, Wang P (2007) Vasoactive hormone adrenomedullin and its binding protein: anti-inflammatory effects by up-regulating peroxisome proliferator-activated receptor-gamma. J Immunol 179:6263–6272PubMedCrossRefGoogle Scholar
  168. 168.
    Li HWR, Liao S-B, Chiu PCN, Yeung WSB, Ng EHY, Cheung ANY, Tang F, O WS (2015) Effects of adrenomedullin on the expression of inflammatory cytokines and chemokines in oviducts from women with tubal ectopic pregnancy: an in-vitro experimental study. Reprod Biol Endocrinol 13:120. PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Ma W, Chabot J-G, Quirion R (2006) A role for adrenomedullin as a pain-related peptide in the rat. Proc Natl Acad Sci 103:16027–16032. PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1:120–130. PubMedCrossRefGoogle Scholar
  171. 171.
    Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441:424–430. PubMedCrossRefGoogle Scholar
  172. 172.
    Atif F, Yousuf S, Stein DG (2015) Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling. J Steroid Biochem Mol Biol 146:62–73. PubMedCrossRefGoogle Scholar
  173. 173.
    Kim JY, Ballato J, Foy P, Hawkins T, Wei Y, Li J, Kim SO (2011) Apoptosis of lung carcinoma cells induced by a flexible optical fiber-based cold microplasma. Biosens Bioelectron 28:333–338. PubMedCrossRefGoogle Scholar
  174. 174.
    Kato H, Shichiri M, Marumo F, Hirata Y (1997) Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells1. Endocrinology 138:2615–2620. PubMedCrossRefGoogle Scholar
  175. 175.
    Oehler MK, Norbury C, Hague S, Rees MCP, Bicknell R (2001) Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth. Oncogene 20:2937–2945. PubMedCrossRefGoogle Scholar
  176. 176.
    Rebuffat P, Forneris ML, Aragona F, Ziolkowska A, Malendowicz LK, Nussdorfer GG (2002) Adrenomedullin and its receptors are expressed in the zona glomerulosa of human adrenal gland: evidence that ADM enhances proliferation and decreases apoptosis in cultured ZG cells. Int J Mol Med 9:119–124PubMedGoogle Scholar
  177. 177.
    Sata M, Kakoki M, Nagata D, et al (2000) Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cyclic GMP-independent mechanism. Hypertens (Dallas, Tex 1979) 36:83–8.Google Scholar
  178. 178.
    Shichiri M, Hirata Y (2003) Regulation of cell growth and apoptosis by adrenomedullin. Hypertens Res 26(Suppl):S9–S14Google Scholar
  179. 179.
    Zündorf G, Reiser G (2011) Calcium dysregulation and homeostasis of neural calcium in the molecular mechanisms of neurodegenerative diseases provide multiple targets for neuroprotection. Antioxid Redox Signal 14:1275–1288. PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Xu Y, Krukoff TL (2005) Adrenomedullin stimulates nitric oxide release from SK-N-SH human neuroblastoma cells by modulating intracellular calcium mobilization. Endocrinology 146:2295–2305. PubMedCrossRefGoogle Scholar
  181. 181.
    Ji S-M, Xue J-M, Wang C, Su SW, He RR (2005) Adrenomedullin reduces intracellular calcium concentration in cultured hippocampal neurons. Sheng Li Xue Bao 57:340–345PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, and IdiSNA, Navarra Institute for Health ResearchUniversity of NavarraPamplonaSpain
  2. 2.Biomarkers and Molecular SignalingCenter for Biomedical Research of La Rioja (CIBIR)LogroñoSpain
  3. 3.Neuroscience AreaBiodonostia Health Research Institute, CIBERNEDSan SebastianSpain
  4. 4.Oncology AreaCenter for Biomedical Research of La Rioja (CIBIR)LogroñoSpain

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