Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer's disease.

Publication Type	Academic Article
Authors	DaRocha-Souto B, Coma M, Pérez-Nievas B, Scotton T, Siao M, Sánchez-Ferrer P, Hashimoto T, Fan Z, Hudry E, Barroeta I, Serenó L, Rodríguez M, Sánchez M, Hyman B, Gómez-Isla T
Journal	Neurobiol Dis
Volume	45
Issue	1
Pagination	425-37
Date Published	09/13/2011
ISSN	1095-953X
Keywords	Alzheimer Disease, Amyloid beta-Peptides, Brain, Glycogen Synthase Kinase 3, Neurites
Abstract	β-Amyloid (Aβ) 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 Aβ, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3β, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3β after exposure to oligomeric Aβ in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3β, even in the absence of Aβ, is sufficient to produce a phenocopy of Aβ-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3β prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3β inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3β inhibition robustly decreased the oligomeric Aβ load in the mouse brain. All these findings support the idea that GSK3β is aberrantly activated by the presence of Aβ, and contributes, at least in part, to the neuronal anatomical derangement associated with Aβ plaques in AD brains and to Aβ pathology itself.
DOI	10.1016/j.nbd.2011.09.002
PubMed ID	21945540
PubMed Central ID	PMC3694284