Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. Critical components of the two AD pathological pathways, Aβ-amyloidosis and Tauopathy, have been considered as therapeutic targets. Among them, much effort is focused on aberrant Tau phosphorylation and targeting Tau-phosphorylating kinases. Methylene blue (MB), a phenothiazine dye that crosses the blood-brain barrier, has been shown to hit multiple molecular targets involved in AD and have beneficial effects in clinical studies. Here we present evidence that microtubule affinity-regulating kinase (MARK4) is a novel target of MB. MB partially rescued the synaptic toxicity in Drosophila larva overexpressing PAR1 (MARK analog). In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. Further studies revealed a two-fold mechanism by MB including down-regulation of MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro. This study highlights the importance of MARK4 as a viable target for Tauopathy and provides fresh insight into the complex mechanism used by MB to treat AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity
It has been shown that PAR1/microtubule affinity-regulating kinase (MARK) is predominantly localized at neuromuscular junction (NMJ) and overexpression (OE) of PAR1 leads to decreased synapse formation and synaptic transmission[20,21], which is mediated by Tau[22]
It has been proposed that aberrant hyperphosphorylation of Tau -likely caused by the imbalance between kinase and phosphatase activities- is the initiating event of a pathogenic cascade that leads to neuronal death[7]
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. In Drosophila, overexpression of PAR1, the fly homolog of MARK kinase, leads to elevated tau phosphorylation at S262 and S356 sites and increased toxicity. A genetic screen to identify modifiers of Tauopathy in a Drosophila model revealed that kinases and phosphatases are the major factors to affect Tau toxicity[6]. These studies suggest that orderly phosphorylation of Tau increases its toxicity and pharmacological intervention of these phosphorylation reactions may represent novel therapeutic strategy for AD treatment[7]. We studied the effect of MB on MARK4 mediated Tau phosphorylation in a Drosophila model as well as in mammalian cell cultures.
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