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

beta-Amyloid (A beta) 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 A beta, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3 beta, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3 beta after exposure to oligomeric A beta in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3 beta, even in the absence of A beta, is sufficient to produce a phenocopy of A beta-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3 beta prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3 beta inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3 beta inhibition robustly decreased the oligomeric A beta load in the mouse brain. All these findings support the idea that GSK3 beta is aberrantly activated by the presence of A beta, and contributes, at least in part, to the neuronal anatomical derangement associated with A beta plaques in AD brains and to A beta pathology itself. (C) 2011 Elsevier Inc. All rights reserved.