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- W2110832568 abstract "Glycogen synthase kinase-3 (GSK-3) isoforms are constitutively active kinases whose activities are involved in the formation of both amyloid plaques and neurofibrillary tangles. Historically, these related enzymes were presumed to be functionally redundant. Using short interfering RNAs (siRNA) to knockdown GSK-3α and GSK-3β in CHO cells, we found an apparent functional difference between GSK-3 isoforms with respect to their roles in producing β-amyloid (Aβ) peptides. A logical next step is to evaluate the endogenous roles of GSK-3 isoforms on Aβ peptide production in vivo. The embryonic lethality of GSK-3β-/- mice, as well as the presumed embryonic lethality of GSK-3α-/- mice, necessitated the creation of conditional knockout mice. Mice containing floxed alleles of GSK-3β have been generated and verified to be functional. In addition, mice containing a floxed GSK-3α allele have been created and are being bred to homozygosity. These mice are being bred with transgenic mice expressing APP and tau, allowing us to evaluate the requirement of GSK-3 isoforms in promoting both plaque and tangle production in vivo. As a prelude to these analyses, we have isolated neural stem cells from floxed GSK-3β mice and verified their ability to differentiate into neurons, astrocytes, and glia. Data regarding APP processing and tau phosphorylation in these neural stem cells will be reported. Finally, we have also analyzed both APP processing and the status of tau phosphorylation in GSK-3α-/-, GSK-3β-/-, and GSK-3α-/-;GSK-3β-/- (double knockout) mouse embryonic stem cells (ESCs). As predicted from previous studies, levels of endogenous APP C-terminal fragments robustly accumulate in GSK-3α-/-;GSK-3β-/- ESCs, indicative of decreased γ-secretase cleavage of APP. Unexpectedly, we still detect tau phosphorylation on sites previously determined to be primarily regulated by GSK-3. In summary, we have utilized cells and animals genetically lacking GSK-3 isoforms in order to study the contribution of these kinases to two of the prominent pathologies found in Alzheimer's disease brains." @default.
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- W2110832568 date "2008-07-01" @default.
- W2110832568 modified "2023-09-27" @default.
- W2110832568 title "O1-03-02: Analyzing the endogenous roles of GSK-3 isoforms in APP processing in GSK-3 deficient cells" @default.
- W2110832568 doi "https://doi.org/10.1016/j.jalz.2008.05.230" @default.
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