RT Journal Article
T1 Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer's disease model
A1 Fernandez-Valenzuela, Juan Jose
A1 Sanchez-Varo, Raquel
A1 Muñoz-Castro, Clara
A1 De Castro, Vanessa
A1 Sanchez-Mejias, Elisabeth
A1 Navarro, Victoria
A1 Jimenez, Sebastian
A1 Nuñez-Diaz, Cristina
A1 Gomez-Arboledas, Angela
A1 Moreno-Gonzalez, Ines
A1 Vizuete, Marisa
A1 Davila, Jose Carlos
A1 Vitorica, Javier
A1 Gutierrez, Antonia
K1 Amyloid
K1 Alzheimer disease
K1 Axonal transport
K1 Brain
K1 Interneurons
K1 Tauopathies
K1 Amiloide
K1 Enfermedad de Alzheimer
K1 Transporte axonal
K1 Encéfalo
K1 Interneuronas
K1 Tauopatías
AB 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.
PB Springer Nature
YR 2020
FD 2020-09-08
LK http://hdl.handle.net/10668/3590
UL http://hdl.handle.net/10668/3590
LA en
NO Fernandez-Valenzuela JJ, Sanchez-Varo R, Muñoz-Castro C, De Castro V, Sanchez-Mejias E, Navarro V, et al. 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
DS RISalud
RD Apr 18, 2025