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Decreased nuclear β‐catenin, tau hyperphosphorylation and neurodegeneration in GSK‐3β conditional transgenic mice
Author(s) -
Lucas José J.,
Hernández Félix,
GómezRamos Pilar,
Morán María A.,
Hen René,
Avila Jesús
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.1.27
Subject(s) - gsk 3 , neurodegeneration , astrocytosis , biology , dentate gyrus , hyperphosphorylation , neuroscience , gsk3b , transgene , microbiology and biotechnology , genetically modified mouse , hippocampal formation , presenilin , alzheimer's disease , pathology , signal transduction , kinase , biochemistry , medicine , central nervous system , disease , gene
Glycogen synthase kinase‐3β (GSK‐3β) has been postulated to mediate Alzheimer's disease tau hyperphosphorylation, β‐amyloid‐induced neurotoxicity and presenilin‐1 mutation pathogenic effects. By using the tet‐regulated system we have produced conditional transgenic mice overexpressing GSK‐3β in the brain during adulthood while avoiding perinatal lethality due to embryonic transgene expression. These mice show decreased levels of nuclear β‐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‐3β results in neurodegeneration and suggest that these mice can be used as an animal model to study the relevance of GSK‐3β deregulation to the pathogenesis of Alzheimer's disease.