Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice

Abstract

Glycogen synthase kinase-3beta (GSK-3beta) has been postulated to mediate Alzheimer's disease tau hyperphosphorylation, beta-amyloid-induced neurotoxicity and presenilin-1 mutation pathogenic effects. By using the tet-regulated system we have produced conditional transgenic mice overexpressing GSK-3beta in the brain during adulthood while avoiding perinatal lethality due to embryonic transgene expression. These mice show decreased levels of nuclear beta-catenin and hyperphosphorylation of tau in hippocampal neurons, the latter resulting in pretangle-like somatodendritic localization of tau. Neurons displaying somatodendritic localization of tau often show abnormal morphologies and detachment from the surrounding neuropil. Reactive astrocytosis and microgliosis were also indicative of neuronal stress and death. This was further confirmed by TUNEL and cleaved caspase-3 immunostaining of dentate gyrus granule cells. Our results demonstrate that in vivo overexpression of GSK-3beta results in neurodegeneration and suggest that these mice can be used as an animal model to study the relevance of GSK-3beta deregulation to the pathogenesis of Alzheimer's disease.

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

“…38 Transgenic mice overexpressing GSK-3b were shown to display t hyperphosphorylation, disrupted microtubules, and apoptotic neurons. 24 These results imply that alterations in the control of GSK-3b expression may occur in the AD brain. Our results also show that immunoreactivities for the nuclear APLP2-CTFs, and for GSK-3b were upregulated in in the AD patients' brain ( Figure 5).…”

“…24 Immunoreacitivities for APLP2-CTFs and GSK-3b are elevated in the AD brain. The localization of APLP2-CTFs and GSK-3b in a total of five AD and four nondemented age-matched control cases was examined.…”

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

“…The abnormal increases in GSK-3 levels and activity have been associated with neuronal apoptosis, hyperphosphorylation of microtubule associated protein tau, and as well as a decline in cognitive performance (Hetman et al, 2002;Mookherjee and Johnson, 2001;Schubert et al, 2004;Stoothoff and Johnson, 2001). Moreover, transgenic mice overexpressing GSK-3β reported to show abnormal tau hyper phosphorylation and increased neuronal apoptosis (Lucas et al, 2001). Recent reports suggest that phosphatidylinositol-3 kinase/protein kinase B (Akt) signaling pathway in the survival of neurons that leads to the inhibition of GSK-3 by increasing Ser9 phosphorylation (Cross et al, 1995).…”

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…126,127 In line with these findings, GSK-3␤ overexpressing transgenic mice showed increased tau phosphorylation and deficits in spatial memory. 128,129 Tau phosphorylation by GSK-3 can be enhanced by A␤ -treatment, which thus provides a possible link between tau and A␤ pathology. 130 GSK-3␤ activity is negatively regulated by phosphorylation at S9 through different kinases (e.g., AKT-protein kinase B).…”