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oai:riuma.uma.es:10630/290142026-02-03T10:53:52Zcom_10630_2254col_10630_37953

00925njm 22002777a 4500 dc Fernández-Valenzuela, Juan José author Sánchez-Varo, Raquel María author Muñoz-Castro, Clara author De Castro Carratalá, Vanessa author Sánchez-Mejías, Elisabeth author Navarro, Victoria author Jimenez, Sebastian author Núñez-Díaz, Cristina author Gómez-Arboledas, Ángela author Moreno-González, Inés author Vizuete, Marisa author Dávila-Cansino, José Carlos author Vitorica Ferrández, Javier author Gutiérrez-Pérez, Antonia author 2020-09-08 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. Fernandez-Valenzuela JJ, Sanchez-Varo R, Muñoz-Castro C, De Castro V, Sanchez-Mejias E, Navarro V, Jimenez S, Nuñez-Diaz C, Gomez-Arboledas A, Moreno-Gonzalez I, Vizuete M, Davila JC, Vitorica J, Gutierrez A. 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. PMID: 32901091; PMCID: PMC7479116. 32901091 https://hdl.handle.net/10630/29014 10.1038/s41598-020-71767-4 Alzheimer, Enfermedad de - Modelos animales Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer's disease model.