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Reduced Adrenomedullin Parallels Microtubule Dismantlement in Frontotemporal Lobar Degeneration

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Abstract

Tau is a microtubule-associated protein highly expressed in neurons with a chief role in microtubule dynamics and axonal maintenance. Adrenomedullin gene (ADM) codifies for various peptides that exert broad range of actions in the body. Previous works in our groups have shown that increased ADM products are positively correlated to microtubule disruption and tau pathology in Alzheimer’s disease brains. In the present study, we explore the involvement of ADM in the neuropathology of frontotemporal lobar degeneration that presents with primary tauopathy (FTLD-tau). Proteins from frontal cortices of FTLD-tau patients and age- and sex-matched non-demented controls were analyzed with antibodies against different microtubule components, including adrenomedullin, and synaptic markers. Tau pathology in frontal cortex from FTLD patients was confirmed. Levels of total βIII-tubulin as well as acetylated and detyrosinated tubulins, two markers of stabilized and aged microtubules, were significantly reduced and directly correlated with PSD95 and proBDNF in FTLD-tau patients when compared to non-demented controls. In contrast, no change in actin cytoskeleton was found. Interestingly, changes in microtubule elements, indicators of disturbed axonal preservation, were accompanied by decreased levels of free adrenomedullin, although no association was found. Altogether, reduced levels of adrenomedullin might not be directly linked to the microtubule pathology of FTLD-tau, but based on previous works, it is suggested that downregulation of ADM might be an adaptive attempt of neurons to mitigate microtubule disruption.

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Acknowledgments

We thank the Brains for Dementia Research (BDR) program for the provision of human brain samples.

Funding Information

H.F. is a recipient of a fellowship from the 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 funded by the Fundación Rioja Salud (FRS).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Navarra, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain

    Hilda Ferrero, Maite Solas & María J. Ramírez

  2. Biomarkers and Molecular Signaling, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain

    Ignacio M. Larrayoz

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

    Alfredo Martínez

  4. Neurosciences Area, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain

    Francisco J. Gil-Bea

  5. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Health Institute Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain

    Francisco J. Gil-Bea

Authors
  1. Hilda Ferrero
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  2. Ignacio M. Larrayoz
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  3. Maite Solas
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  4. Alfredo Martínez
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  5. María J. Ramírez
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  6. Francisco J. Gil-Bea
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Corresponding author

Correspondence to Francisco J. Gil-Bea.

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Informed consent was obtained from the patients’ next of kin before collection of brains, and the study was approved by the UK National Research Ethics Service.

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Ferrero, H., Larrayoz, I.M., Solas, M. et al. Reduced Adrenomedullin Parallels Microtubule Dismantlement in Frontotemporal Lobar Degeneration. Mol Neurobiol 55, 9328–9333 (2018). https://doi.org/10.1007/s12035-018-1079-8

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  • DOI: https://doi.org/10.1007/s12035-018-1079-8

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