Artículo
Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer’s disease model
Autor/es | Fernández Valenzuela, Juan José
Muñoz Castro, Clara Jiménez Muñoz, Sebastián Vizuete Chacón, María Luisa Vitorica Ferrández, Francisco Javier Gutierrez Pérez, Antonia |
Departamento | Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular |
Fecha de publicación | 2020 |
Fecha de depósito | 2021-04-22 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Instituto de Salud Carlos III (ISCiii) de España European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) Centro de Investigación Biomédica en Red (CIBERNED) |
Identificador del proyecto | PI15/00796
PI18/01557 PI15/00957 PI18/01556 CB06/05/1116 CB06/05/0094 |
Cita | Fernández Valenzuela, J.J., Muñoz Castro, ., Jiménez Muñoz, S., Vizuete Chacón, M.L., Vitorica Ferrández, F.J. y Gutierrez Pérez, A. (2020). Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer’s disease model. Scientific Reports, 10, 14776. |
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s41598-020-71767-4.pdf | 4.967Mb | [PDF] | Ver/ | |