title: Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer's disease.
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.
authors.affiliation: Neurology Department, Massachusetts General Hospital, Harvard University, Boston, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: DaRocha-Souto
authors.forename: M
authors.initials: M
authors.lastname: Coma
authors.forename: B G
authors.initials: BG
authors.lastname: Pérez-Nievas
authors.forename: T C
authors.initials: TC
authors.lastname: Scotton
authors.forename: M
authors.initials: M
authors.lastname: Siao
authors.forename: P
authors.initials: P
authors.lastname: Sánchez-Ferrer
authors.forename: T
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Z
authors.initials: Z
authors.lastname: Fan
authors.forename: E
authors.initials: E
authors.lastname: Hudry
authors.forename: I
authors.initials: I
authors.lastname: Barroeta
authors.forename: L
authors.initials: L
authors.lastname: Serenó
authors.forename: M
authors.initials: M
authors.lastname: Rodríguez
authors.forename: M B
authors.initials: MB
authors.lastname: Sánchez
authors.forename: B T
authors.initials: BT
authors.lastname: Hyman
authors.forename: T
authors.initials: T
authors.lastname: Gómez-Isla
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008822:Mice, Transgenic; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3