Activation of glycogen synthase kinase-3 beta mediates ß-amyloid induced neuritic damage in Alzheimer's disease
Por:
DaRocha-Souto B., Coma M., Pérez-Nievas B.G., Scotton T.C., Siao M., Sánchez-Ferrer P., Hashimoto T., Fan Z., Hudry E., Barroeta I., Serenó L., Rodríguez M., Sánchez M.B., Hyman B.T., Gómez-Isla T.
Publicada:
1 ene 2012
Resumen:
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.
Filiaciones:
DaRocha-Souto B.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Coma M.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Pérez-Nievas B.G.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Scotton T.C.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Siao M.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Sánchez-Ferrer P.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Hashimoto T.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Fan Z.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Hudry E.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Barroeta I.:
Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Serenó L.:
Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Rodríguez M.:
Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Sánchez M.B.:
Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Hyman B.T.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Gómez-Isla T.:
Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, United States
Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Green Accepted, All Open Access; Green
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