2. Academic Validation
  3. Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer's disease model

Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer's disease model

  • Sci Rep. 2020 Sep 8;10(1):14776. doi: 10.1038/s41598-020-71767-4.
Juan Jose Fernandez-Valenzuela  # 1 2,  Raquel Sanchez-Varo  # 1 2,  Clara Muñoz-Castro 2 3 4,  Vanessa De Castro 1,  Elisabeth Sanchez-Mejias 1 2,  Victoria Navarro 2 3 4,  Sebastian Jimenez 2 3 4,  Cristina Nuñez-Diaz 1 2,  Angela Gomez-Arboledas 1 2,  Ines Moreno-Gonzalez 1 2,  Marisa Vizuete 2 3 4,  Jose Carlos Davila 1 2,  Javier Vitorica 5 6 7,  Antonia Gutierrez 8 9
Affiliations

Affiliations

  • 1 Dpto. Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga-IBIMA, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Málaga, Spain.
  • 2 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
  • 3 Dpto. Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, C/Prof. Garcia Gonzalez 2, 41012, Sevilla, Spain.
  • 4 Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio/CSIC, Universidad de Sevilla, Sevilla, Spain.
  • 5 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. vitorica@us.es.
  • 6 Dpto. Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, C/Prof. Garcia Gonzalez 2, 41012, Sevilla, Spain. vitorica@us.es.
  • 7 Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio/CSIC, Universidad de Sevilla, Sevilla, Spain. vitorica@us.es.
  • 8 Dpto. Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga-IBIMA, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Málaga, Spain. agutierrez@uma.es.
  • 9 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. agutierrez@uma.es.
  • # Contributed equally.
PMID: 32901091 DOI: 10.1038/s41598-020-71767-4
Abstract

In Alzheimer's disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, the effect of microtubule stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aβ accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aβ levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between Cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aβ pathology.

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