期刊
EMBO JOURNAL
卷 20, 期 1-2, 页码 27-39出版社
OXFORD UNIV PRESS
DOI: 10.1093/emboj/20.1.27
关键词
Alzheimer's disease; beta-catenin; conditional transgenic mice; GSK-3 beta; tau phosphorylation
Glycogen synthase kinase-3 beta (GSK-3 beta) 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-3 beta 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-3 beta results in neurodegeneration and suggest that these mice can be used as an animal model to study the relevance of GSK-3 beta deregulation to the pathogenesis of Alzheimer's disease.
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