Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine 
kinase that is particularly abundant in the CNS. Dysregulation of GSK-3 activity 
is believed to play a key role in the pathogenesis of CNS chronic disorders such 
as Alzheimer's disease (AD), bipolar disorder, and Huntington's disease, and of 
metabolic disorders such as type II diabetes. Accordingly, GSK-3 inhibitors have 
been postulated as therapeutic tools for these diseases. Interestingly, 
pathophysiological and pharmacological regulation of GSK-3 is affected by an 
amplification mechanism that applies both to inhibition and activation. The 
possibility therefore exists that sustained inhibition or activation might 
persist after cessation of the initial trigger. Regarding AD, GSK-3 has been 
shown to accumulate in pretangle neurons. Furthermore, GSK-3 phosphorylates tau 
in most serine and threonine residues hyperphosphorylated in PHF (paired helical 
filament)-tau and GSK-3 activity contributes both to beta-amyloid production and 
to beta-amyloid-mediated neuronal death. In good agreement, mice with 
conditional overexpression of GSK-3 in forebrain neurons (Tet/GSK-3beta mice) 
recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, 
apoptotic neuronal death, and reactive astrocytosis as well as spatial learning 
deficit. Here, we exploit the conditional system used to generate Tet/GSK-3beta 
mice to explore whether the biochemical, histopathological, and behavioral 
consequences of increased GSK-3 activity are susceptible to revert after 
restoration of normal GSK-3 levels. Here, we show that transgene shutdown in 
symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, 
diminished neuronal death, and suppression of the cognitive deficit, thus 
further supporting the potential of GSK-3 inhibitors for AD therapeutics.