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- W2061111904 abstract "The role of tau phosphorylation in the evolution of Alzheimer's Disease (AD) is gaining prominence offering new therapeutic targets. Casein kinase 1 delta (CK1d) is required to generate hyperphosphorylated tau through direct phosphorylation of specific pathogenic sites, by priming tau for subsequent hyperphosphorylation by GSK3 b and through the direct activation of CDK5, another tau kinase. CK1d also plays important roles in other features of AD such as cell cycle control, neuritic sprouting and sleep dysfunction, further suggesting it as an important therapeutic target. The closely related casein kinase 1 epsilon (CK1e) which has a virtually identical ATP binding site has also been shown to regulate gamma-secretase activity and thus the production of toxic amyloid. We have developed two selective CK1d/e inhibitors, PS110 & PS278–05, using several rounds of in silico design and in vitro testing. TMHT mice aged 8.5 months were treated once daily with vehicle or vehicle plus active compound at 30 mg/mg. Cogntive performance was tested using the Morris Water Maze on days 50–54 and animals sacrificed at day 56. Levels of tau phosphorylation at several pathogenic sites were determined using Western blot (pT231 & pS396) and mass spectrometry methods (pS46, pT50, pS113, pT181, pS199, pT231, pS262, pS396, pS404 & pS433) and levels compared between animals treated with vehicle or active compounds. Treatment with PS110 and PS278 led to improved cognitive performance in Morris Water Maze with no overt toxicity issues. A significant loss of phosphate at several human tau sites known to be phosphorylated by GSK3 b after upstream CK1d priming, or directly by CDK5 was detected by both immunological and mass spectrometry methods in PS110 treated animals. Interestingly we also see a general loss of soluble heat stable tau in treated animals suggesting CK1d/e inhibition stops the production and accumulation of hyperphosphorylated tau in this model. The continued failure of therapies targeting single aspects of AD pathology suggests a multi-pathway approach is required. Preliminary data with selective CK1d/e inhibitors suggests we are intervening through multiple modes of action. Implications of these data for the development of PS110 and PS278–05 towards human trials will be discussed." @default.
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- W2061111904 date "2013-07-01" @default.
- W2061111904 modified "2023-09-27" @default.
- W2061111904 title "P4-410: Improved cognitive behavior in an Alzheimer's model through multimodal reduction of tau phosphorylation and accumulation in hippocampus by orally available inhibitors of casein kinase 1 delta/epsilon" @default.
- W2061111904 doi "https://doi.org/10.1016/j.jalz.2013.08.243" @default.
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