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- W2746093721 abstract "The discovery of mutations within the MAPT gene has demonstrated that tau accumulation is sufficient to cause neuronal loss and clinical dementia in and of itself in the absence of amyloid deposition. Recent studies have demonstrated that induction of molecular chaperones leads to increased degradation of abnormal tau suggesting that other therapeutic strategies are possible for the treatment of tauopathy. To develop cell–based assays to screen for compounds that reduce abnormal tau levels with concomitant toxicity estimates, and utilize a novel panel of Hsp90 inhibitors, that induce the de novo synthesis of multiple HSPs, as proof of principle. The ultimate goal of these studies is to test the most promising compounds in vivo. We have developed novel 96–well microplate–based In–Cell Western assays that utilized near–infrared imaging to analyze the effects of these compounds on tau biology in cell culture. We demonstrated that compounds causing potent HSP elevations in tau over–expressing and untransfected cells produced concomitant reductions in tau species with pathological changes in phosphorylation state and conformation. The enhanced clearance of pathological tau species was primarily mediated via the proteasome, while the lysosomal system seems to play a minimal role. Interestingly, tau that is phosphorylated at S262/S356 by microtubule affinity regulating kinase (MARK) was minimally affected by HSP90 modulation compared with tau phosphorylated at S202/T205 (CP13) and S396/S404 (PHF–1). These data suggest that the molecular chaperone system may be able to distinguish normal from pathological tau phosphorylation. Preliminary in vivo work has demonstrated that one of these HSP90 inhibitors possessed sufficient blood brain barrier permeability to elicit sustained HSP elevation in the brains of mice, providing a unique tool to investigate the potential for therapeutic relevance of this strategy in neurodegenerative disease and therefore prompting further studies using transgenic mouse models of tauopathy." @default.
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- W2746093721 date "2006-07-01" @default.
- W2746093721 modified "2023-09-26" @default.
- W2746093721 title "P3-319: Manipulating components of the heat shock response as a therapeutic strategy for tauopathies" @default.
- W2746093721 doi "https://doi.org/10.1016/j.jalz.2006.05.1589" @default.
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