The glycogen synthase kinase-3β (GSK3β) pathway plays an important role in mediating neuronal fate and synaptic plasticity. In Alzheimer's disease (AD), abnormal activation of this pathway might play an important role in neurodegeneration, and compounds such as lithium that modulate GSK3β activity have been shown to reduce amyloid production and tau phosphorylation in amyloid precursor protein (APP) transgenic (tg) mice. However, it is unclear whether regulation of GSK3β is neuroprotective in APP tg mice. In this context, the main objective of the present study was to determine whether pharmacological or genetic manipulations that block the GSK3β pathway might ameliorate the neurodegenerative alterations in APP tg mice and to better understand the mechanisms involved. For this purpose, two sets of experiments were performed. First, tg mice expressing mutant human APP under the Thy1 promoter (hAPP tg) were treated with either lithium chloride or saline alone. Second, hAPP tg mice were crossed with GSK3β tg mice, in which overexpression of this signaling molecule results in a dominant-negative (DN) effect with inhibition of activity. hAPP tg mice that were treated with lithium or that were crossed with DN-GSK3β tg mice displayed improved performance in the water maze, preservation of the dendritic structure in the frontal cortex and hippocampus, and decreased tau phosphorylation. Moreover, reduced activation of GSK3β was associated with decreased levels of APP phosphorylation that resulted in decreased amyloid-β production. In conclusion, the present study showed that modulation of the GSK3β signaling pathway might also have neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that GSK3β might be a suitable target for the treatment of AD. Copyright © 2007 Society for Neuroscience.