Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice.
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.
Centro de Biología Molecular 'Severo Ochoa', CSIC/Universidad Autónoma de Madrid, Departamento de Morfología, Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
J J
JJ
Lucas
F
F
Hernández
P
P
Gómez-Ramos
M A
MA
Morán
R
R
Hen
J
J
Avila
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002522:Chlorocebus aethiops; D003433:Crosses, Genetic; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D005911:Gliosis; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators; D014162:Transfection; D051176:beta Catenin; D016875:tau Proteins / Q000378:metabolism*
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D051176:beta Catenin; D016875:tau Proteins; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3