Activation of glycogen synthase kinase-3 beta mediates ß-amyloid induced neuritic damage in Alzheimer's disease
ß-Amyloid (Aß) plaques in Alzheimer (AD) brains are surrounded by severe dendritic and axonal changes, including local spine loss, axonal swellings and distorted neurite trajectories. Whether and how plaques induce these neuropil abnormalities remains unknown. We tested the hypothesis that oligomeri...
| Authors: | , , , , , , , , , , , , , , |
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| Format: | article |
| Status: | Published version |
| Publication Date: | 2012 |
| Country: | España |
| Institution: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repository: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p11611 |
| Online Access: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11611 https://europepmc.org/article/MED/21945540 |
| Access Level: | Open access |
| Keyword: | amyloid beta protein brain derived neurotrophic factor cyclic AMP responsive element binding protein glycogen synthase kinase 3 glycogen synthase kinase 3 inhibitor tau protein Alzheimer disease animal cell animal experiment animal model animal tissue article brain cell cell loss controlled study drug efficacy enzyme activation enzyme activity enzyme phosphorylation gene expression mouse nerve cell nerve cell lesion nerve cell plasticity nerve degeneration neurotoxicity nonhuman pathogenesis pharmacological blocking phenotype priority journal Alzheimer Disease Amyloid beta-Peptides Animals Brain Cells, Cultured Dendritic Spines Glycogen Synthase Kinase 3 Mice Mice, Transgenic Neurites Neurons tau Proteins |
| Summary: | ß-Amyloid (Aß) plaques in Alzheimer (AD) brains are surrounded by severe dendritic and axonal changes, including local spine loss, axonal swellings and distorted neurite trajectories. Whether and how plaques induce these neuropil abnormalities remains unknown. We tested the hypothesis that oligomeric assemblies of Aß, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3ß, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3ß after exposure to oligomeric Aß in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3ß, even in the absence of Aß, is sufficient to produce a phenocopy of Aß-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3ß prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3ß inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3ß inhibition robustly decreased the oligomeric Aß load in the mouse brain. All these findings support the idea that GSK3ß is aberrantly activated by the presence of Aß, and contributes, at least in part, to the neuronal anatomical derangement associated with Aß plaques in AD brains and to Aß pathology itself. © 2011 Elsevier Inc. |
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