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

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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.
MeSH Terms
Medical Subject Headings::Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease
Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cytoplasmic Streaming::Axonal Transport
Medical Subject Headings::Psychiatry and Psychology::Mental Disorders::Delirium, Dementia, Amnestic, Cognitive Disorders::Cognition Disorders
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Lactones::Macrolides::Epothilones
Medical Subject Headings::Check Tags::Female
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic
Medical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Cytoskeleton::Microtubules
Medical Subject Headings::Anatomy::Nervous System::Neurons
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype
Medical Subject Headings::Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Mitosis Modulators::Antimitotic Agents::Tubulin Modulators
Medical Subject Headings::Diseases::Animal Diseases::Disease Models, Animal
DeCS Terms
CIE Terms
Amyloid, Alzheimer disease, Axonal transport, Brain, Interneurons, Tauopathies, Amiloide, Enfermedad de Alzheimer, Transporte axonal, Encéfalo, Interneuronas, Tauopatías
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