The
glycogen synthase kinase-3beta (
GSK3beta) 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
GSK3beta 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
GSK3beta 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
GSK3beta 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
GSK3beta 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-GSK3beta 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
GSK3beta was associated with decreased levels of APP phosphorylation that resulted in decreased
amyloid-beta production. In conclusion, the present study showed that modulation of the
GSK3beta signaling pathway might also have
neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that
GSK3beta might be a suitable target for the treatment of AD.