Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer’s disease model
| Autor: | Victoria Navarro, Javier Vitorica, Cristina Nuñez-Diaz, Sebastian Jimenez, Elisabeth Sanchez-Mejias, Angela Gomez-Arboledas, Clara Muñoz-Castro, Marisa Vizuete, Raquel Sanchez-Varo, Juan Jose Fernandez-Valenzuela, Ines Moreno-Gonzalez, Jose Carlos Davila, Antonia Gutierrez, Vanessa De Castro |
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| Přispěvatelé: | Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Instituto de Salud Carlos III (ISCiii) de España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Centro de Investigación Biomédica en Red (CIBERNED), Instituto de Salud Carlos III, European Commission, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Universidad de Málaga, Ministerio de Ciencia, Innovación y Universidades (España), [Fernandez-Valenzuela,JJ, Sanchez-Varo,R, De Castro,V, Sanchez-Mejias,E, Nuñez-Diaz,C, Gomez-Arboledas,A, Moreno-Gonzalez,I, Davila,JC, Gutierrez,A] Dpto. Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga‑IBIMA, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain. [Fernandez-Valenzuela,JJ, Muñoz-Castro,C, Navarro,V, Jimenez,S, Vizuete,M, Vitorica,J, Gutierrez,A] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Muñoz-Castro,C, Vitorica,J] Dpto. Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain. [Muñoz-Castro,C, Vitorica,J] Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio/CSIC, Universidad de Sevilla, Sevilla, Spain., This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI15/00796 and PI18/01557 (both to AG), PI15/00957 and PI18/01556 (both to JV), and CIBERNED (CB06/05/1116 to AG and CB06/05/0094 to JV), by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). JJFV and CMC were supported by FPU PhD fellowships (Spanish Ministry of Science, Innovation and Universities). RSV held a postdoctoral contract from Malaga University. IMG is recipient of a senior postdoctoral contract from Ramon y Cajal Program (Spain Government). |
| Rok vydání: | 2020 |
| Předmět: |
Male
Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings] Interneuronas Psychiatry and Psychology::Mental Disorders::Delirium Dementia Amnestic Cognitive Disorders::Cognition Disorders [Medical Subject Headings] lcsh:Medicine Hippocampal formation Chemicals and Drugs::Organic Chemicals::Lactones::Macrolides::Epothilones [Medical Subject Headings] Axonal Transport Microtubules Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] Mice Enfermedad de Alzheimer Organisms::Eukaryota::Animals [Medical Subject Headings] Organisms::Eukaryota::Animals::Animal Population Groups::Animals Genetically Modified::Mice Transgenic [Medical Subject Headings] lcsh:Science Anatomy::Nervous System::Neurons [Medical Subject Headings] Neurons Tauopatías Multidisciplinary Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies [Medical Subject Headings] Neurodegeneration Brain Tubulin Modulators Phenotype Tauopathies Encéfalo Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Cytoskeleton::Microtubules [Medical Subject Headings] GABAergic Female Intracellular Amyloid Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease [Medical Subject Headings] Transporte axonal Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Mitosis Modulators::Antimitotic Agents::Tubulin Modulators [Medical Subject Headings] Check Tags::Male [Medical Subject Headings] Mice Transgenic Biology Neuroprotection Article Interneurons Alzheimer Disease Microtubule Extracellular medicine Animals Humans Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cytoplasmic Streaming::Axonal Transport [Medical Subject Headings] Amiloide lcsh:R medicine.disease Cellular neuroscience Diseases::Animal Diseases::Disease Models Animal [Medical Subject Headings] Disease Models Animal Check Tags::Female [Medical Subject Headings] Epothilones Axoplasmic transport Diseases of the nervous system lcsh:Q Cognition Disorders Neuroscience |
| Zdroj: | idUS: Depósito de Investigación de la Universidad de Sevilla Universidad de Sevilla (US) Scientific Reports idUS. Depósito de Investigación de la Universidad de Sevilla instname Digital.CSIC. Repositorio Institucional del CSIC Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020) |
| ISSN: | 2045-2322 |
| Popis: | 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. This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI15/00796 and PI18/01557 (both to AG), PI15/00957 and PI18/01556 (both to JV), and CIBERNED (CB06/05/1116 to AG and CB06/05/0094 to JV); by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). JJFV and CMC were supported by FPU PhD fellowships (Spanish Ministry of Science, Innovation and Universities). RSV held a postdoctoral contract from Malaga University. IMG is recipient of a senior postdoctoral contract from Ramon y Cajal Program (Spain Government). |
| Databáze: | OpenAIRE |
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