title: Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment.
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.
authors.affiliation: Biomaterial and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Sun
authors.affiliation: Biomaterial and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, California, USA.|Gwangju Center, Korea Basic Science Institute, Gwangju 61186, Korea.
authors.forename: Seongsoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: Biomaterial and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Huang
authors.affiliation: Biomaterial and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Biomaterial and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Inayathullah
authors.affiliation: Biomaterial and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Kwang-Min
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Biomaterial and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Tang
authors.affiliation: War Related Illness and Injury Study Center (WRIISC), VA Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: J Wesson
authors.initials: JW
authors.lastname: Ashford
authors.affiliation: Biomaterial and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001399:Azure Stains / Q000494:pharmacology; D029721:Drosophila Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007814:Larva; D008751:Methylene Blue / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001399:Azure Stains; D029721:Drosophila Proteins; C054369:MAPT protein, human; D016875:tau Proteins; C000599422:tau protein, Drosophila; C483047:MARK4 protein, human; D017346:Protein Serine-Threonine Kinases; C045363:Azure C; D008751:Methylene Blue