Journal Article

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

Muñoz Castro, Clara, Vitorica Ferrández, Francisco Javier, Gutierrez Pérez, Antonia, Fernández Valenzuela, Juan José, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Vizuete Chacón, María Luisa, Jiménez Muñoz, Sebastián, Centro de Investigación Biomédica en Red (CIBERNED)

2020

Overview

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.

• Publisher: Nature Research,Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1689 / 631/378/87 / Alzheimer Disease - complications / Animals / Axonal Transport / Cognition Disorders - etiology / Cognition Disorders - pathology / Cognition Disorders - prevention & control / Crystal structure / Disease Models, Animal / DNA-directed DNA polymerase / DNA-directed RNA polymerase / Epothilones - pharmacology / Female / Humanities and Social Sciences / Humans / Male / Mice / Mice, Transgenic / Microtubules - chemistry / Microtubules - drug effects / multidisciplinary / Neurons - metabolism / Neurons - pathology / Okazaki fragments / Pathology / Phenotype / Primase / Primers / Replication forks / Replication initiation / RNA polymerase / Science / Science (multidisciplinary) / Tauopathies - etiology / Tauopathies - pathology / Tauopathies - prevention & control / Transcription / Tubulin Modulators - pharmacology