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Increased Levels of Brain Adrenomedullin in the Neuropathology of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.

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References

  1. Hernandez F, Lucas JJ, Avila J (2013) GSK3 and tau: two convergence points in Alzheimer’s disease. J Alzheimers Dis 33(Suppl 1):S141–S144

    PubMed  Google Scholar 

  2. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344

    Article  CAS  PubMed  Google Scholar 

  3. Buerger K, Uspenskaya O, Hartmann O et al (2011) Prediction of Alzheimer’s disease using midregional proadrenomedullin and midregional proatrial natriuretic peptide: a retrospective analysis of 134 patients with mild cognitive impairment. J Clin Psychiatry 72:556–563

    Article  CAS  PubMed  Google Scholar 

  4. 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

    Article  PubMed  Google Scholar 

  5. Pérez-Castells J, Martín-Santamaría S, Nieto L et al (2012) Structure of micelle-bound adrenomedullin: a first step toward the analysis of its interactions with receptors and small molecules. Biopolymers 97:45–53

    Article  PubMed  Google Scholar 

  6. López J, Martínez A (2002) Cell and molecular biology of the multifunctional peptide, adrenomedullin. Int Rev Cytol 221:1–92

    Article  PubMed  Google Scholar 

  7. 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 853:245–268

    Article  CAS  PubMed  Google Scholar 

  8. Xu Y, Krukoff TL (2004) Adrenomedullin in the rostral ventrolateral medulla increases arterial pressure and heart rate: roles of glutamate and nitric oxide. Am J Physiol Regul Integr Comp Physiol 287:R729–R734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sackett DL, Ozbun L, Zudaire E et al (2008) Intracellular proadrenomedullin-derived peptides decorate the microtubules and contribute to cytoskeleton function. Endocrinology 149:2888–2898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Larráyoz IM, Martínez A (2012) Proadrenomedullin N-terminal 20 peptide increases kinesin’s velocity both in vitro and in vivo. Endocrinology 153:1734–1742

    Article  PubMed  Google Scholar 

  11. Vergaño-Vera E, Fernández AP, Hurtado-Chong A et al (2010) Lack of adrenomedullin affects growth and differentiation of adult neural stem/progenitor cells. Cell Tissue Res 340:1–11

    Article  PubMed  Google Scholar 

  12. Fernandez AP, Masa JS, Guedan MA et al (2016) Adrenomedullin expression in Alzheimer’s brain. Curr Alzheimer Res 13:428–438

    Article  CAS  PubMed  Google Scholar 

  13. Kirvell SL, Esiri M, Francis PT (2006) Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer’s disease. J Neurochem 98:939–950

    Article  CAS  PubMed  Google Scholar 

  14. Aisa B, Gil-Bea FJ, Solas M et al (2010) Altered NCAM expression associated with the cholinergic system in Alzheimer’s disease. J Alzheimers Dis 20:659–668

    Article  CAS  PubMed  Google Scholar 

  15. Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M et al (2005) Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease. Neuropsychologia 43:442–449

    Article  CAS  PubMed  Google Scholar 

  16. Morgenthaler NG, Struck J, Alonso C, Bergmann A (2005) Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 51:1823–1829

    Article  CAS  PubMed  Google Scholar 

  17. Strzyz P (2016) Post-translational modifications: extension of the tubulin code. Nat Rev Mol Cell Biol 17:609

    Article  CAS  PubMed  Google Scholar 

  18. Mungas D (1991) In-office mental status testing: a practical guide. Geriatrics 46:54–58 63, 66

    CAS  PubMed  Google Scholar 

  19. Vu HT, Akatsu H, Hashizume Y et al (2017) Increase in α-tubulin modifications in the neuronal processes of hippocampal neurons in both kainic acid-induced epileptic seizure and Alzheimer’s disease. Sci Rep 7:40205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rønn LC, Berezin V, Bock E The neural cell adhesion molecule in synaptic plasticity and ageing. Int J Dev Neurosci 18:193–199

  21. Kiss JZ, Muller D (2001) Contribution of the neural cell adhesion molecule to neuronal and synaptic plasticity. Rev Neurosci 12:297–310

    Article  CAS  PubMed  Google Scholar 

  22. Walmod PS, Kolkova K, Berezin V, Bock E (2004) Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem Res 29:2015–2035

    Article  CAS  PubMed  Google Scholar 

  23. Kleene R, Schachner M (2004) Glycans and neural cell interactions. Nat Rev Neurosci 5:195–208

    Article  CAS  PubMed  Google Scholar 

  24. Montag-Sallaz M, Schachner M, Montag D (2002) Misguided axonal projections, neural cell adhesion molecule 180 mRNA upregulation, and altered behavior in mice deficient for the close homolog of L1. Mol Cell Biol 22:7967–7981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Aisa B, Elizalde N, Tordera R et al (2009) Effects of neonatal stress on markers of synaptic plasticity in the hippocampus: implications for spatial memory. Hippocampus 19:1222–1231

    Article  CAS  PubMed  Google Scholar 

  26. Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179

    Article  PubMed  Google Scholar 

  27. Mikkonen M, Soininen H, Tapiola T et al (1999) Hippocampal plasticity in Alzheimer’s disease: changes in highly polysialylated NCAM immunoreactivity in the hippocampal formation. Eur J Neurosci 11:1754–1764

    Article  CAS  PubMed  Google Scholar 

  28. Mikkonen M, Soininen H, Alafuzof I, Miettinen R (2001) Hippocampal plasticity in Alzheimer’s disease. Rev Neurosci 12:311–325

    Article  CAS  PubMed  Google Scholar 

  29. Gillian AM, Brion JP, Breen KC (1994) Expression of the neural cell adhesion molecule (NCAM) in Alzheimer’s disease. Neurodegeneration 3:283–291

    CAS  PubMed  Google Scholar 

  30. Jin K, Peel AL, Mao XO et al (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci 101:343–347

    Article  CAS  PubMed  Google Scholar 

  31. Strekalova H, Buhmann C, Kleene R et al (2006) Elevated levels of neural recognition molecule L1 in the cerebrospinal fluid of patients with Alzheimer disease and other dementia syndromes. Neurobiol Aging 27:1–9

    Article  CAS  PubMed  Google Scholar 

  32. Todaro L, Puricelli L, Gioseffi H et al (2004) Neural cell adhesion molecule in human serum. Increased levels in dementia of the Alzheimer type. Neurobiol Dis 15:387–393

    Article  CAS  PubMed  Google Scholar 

  33. Yew DT, Li WP, Webb SE et al (1999) Neurotransmitters, peptides, and neural cell adhesion molecules in the cortices of normal elderly humans and Alzheimer patients: a comparison. Exp Gerontol 34:117–133

    Article  CAS  PubMed  Google Scholar 

  34. Calsolaro V, Edison P (2016) Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement 12:719–732

    Article  PubMed  Google Scholar 

  35. Francis PT (2003) Glutamatergic systems in Alzheimer’s disease. Int J Geriatr Psychiatry 18:S15–S21

    Article  PubMed  Google Scholar 

  36. Francis PT, Ramírez MJ, Lai MK (2010) Neurochemical basis for symptomatic treatment of Alzheimer’s disease. Neuropharmacology 59:221–229

    Article  CAS  PubMed  Google Scholar 

  37. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  CAS  PubMed  Google Scholar 

  38. Garcia-Alloza M, Tsang SW, Gil-Bea FJ et al (2006) Involvement of the GABAergic system in depressive symptoms of Alzheimer’s disease. Neurobiol Aging 27:1110–1117

    Article  CAS  PubMed  Google Scholar 

  39. Cheung BMY, Ong KL, Tso AWK et al (2011) Plasma adrenomedullin level is related to a single nucleotide polymorphism in the adrenomedullin gene. Eur J Endocrinol 165:571–577

    Article  CAS  PubMed  Google Scholar 

  40. Martínez-Herrero S, Martínez A (2013) Cancer protection elicited by a single nucleotide polymorphism close to the adrenomedullin gene. J Clin Endocrinol Metab 98:E807–E810

    Article  PubMed  Google Scholar 

  41. Martínez A, Weaver C, López J et al (1996) Regulation of insulin secretion and blood glucose metabolism by adrenomedullin. Endocrinology 137:2626–2632

    Article  PubMed  Google Scholar 

  42. Ishikawa T, Chen J, Wang J et al (2003) Adrenomedullin antagonist suppresses in vivo growth of human pancreatic cancer cells in SCID mice by suppressing angiogenesis. Oncogene 22:1238–1242

    Article  CAS  PubMed  Google Scholar 

  43. Martínez A, Julián M, Bregonzio C et al (2004) Identification of vasoactive nonpeptidic positive and negative modulators of adrenomedullin using a neutralizing antibody-based screening strategy. Endocrinology 145:3858–3865

    Article  PubMed  Google Scholar 

  44. Roldós V, Carbajo RJ, Schott A-K et al (2012) Identification of first proadrenomedullin N-terminal 20 peptide (PAMP) modulator by means of virtual screening and NMR interaction experiments. Eur J Med Chem 55:262–272

    Article  PubMed  Google Scholar 

  45. Hickman RA, Faustin A, Wisniewski T (2016) Alzheimer disease and its growing epidemic: risk factors, biomarkers, and the urgent need for therapeutics. Neurol Clin 34:941–953

    Article  PubMed  PubMed Central  Google Scholar 

  46. Barbe C, Morrone I, Novella JL et al (2016) Predictive factors of rapid cognitive decline in patients with Alzheimer disease. Dement Geriatr Cogn Dis Extra 6:549–558

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

H.F. is a recipient of a fellowship from Ministerio de Educación y Ciencia (FPU). I.M.L. and A.M. are funded by Fundación Rioja Salud (FRS).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain

    Hilda Ferrero, Eva Martisova, Maite Solas, Francisco J. Gil-Bea & María J. Ramírez

  2. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain

    Hilda Ferrero, Eva Martisova, Maite Solas, Francisco J. Gil-Bea & María J. Ramírez

  3. Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain

    Ignacio M. Larrayoz & Alfredo Martínez

  4. Wolfson Centre for Age-Related Diseases, King’s College, London, UK

    David R. Howlett & Paul T. Francis

  5. Neuroscience Area, CIBERNED, Biodonostia Health Research Institute, San Sebastian, Spain

    Francisco J. Gil-Bea

  6. Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden

    Francisco J. Gil-Bea

Authors
  1. Hilda Ferrero
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  2. Ignacio M. Larrayoz
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  3. Eva Martisova
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  9. María J. Ramírez
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Correspondence to María J. Ramírez.

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Ferrero, H., Larrayoz, I.M., Martisova, E. et al. Increased Levels of Brain Adrenomedullin in the Neuropathology of Alzheimer’s Disease. Mol Neurobiol 55, 5177–5183 (2018). https://doi.org/10.1007/s12035-017-0700-6

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  • DOI: https://doi.org/10.1007/s12035-017-0700-6

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