Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer’s disease treatment
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 phos...
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| Veröffentlicht in: | Scientific reports 2016-10, Vol.6 (1), p.34784, Article 34784 |
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| description | 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. |
| doi_str_mv | 10.1038/srep34784 |
| format | Article |
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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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep34784</identifier><identifier>PMID: 27708431</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/45/275 ; 631/92/609 ; Alzheimer's disease ; Amyloidosis ; Blood-brain barrier ; Heterogeneity ; Humanities and Social Sciences ; Kinases ; Larvae ; Medical treatment ; Methylene blue ; multidisciplinary ; Neurodegenerative diseases ; Phenothiazine ; Phosphorylation ; Proteasomes ; Protein folding ; Science ; Tau protein ; Toxicity ; Ubiquitin</subject><ispartof>Scientific reports, 2016-10, Vol.6 (1), p.34784, Article 34784</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group Oct 2016</rights><rights>Copyright © 2016, The Author(s) 2016 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-904c8f775192f9ae4bf095a16a25ddaed6a393bcb8a098cd9f0361fd121fa6603</citedby><cites>FETCH-LOGICAL-c504t-904c8f775192f9ae4bf095a16a25ddaed6a393bcb8a098cd9f0361fd121fa6603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052533/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052533/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41098,42167,51553,53768,53770</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27708431$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Wenchao</creatorcontrib><creatorcontrib>Lee, Seongsoo</creatorcontrib><creatorcontrib>Huang, Xiaoran</creatorcontrib><creatorcontrib>Liu, Song</creatorcontrib><creatorcontrib>Inayathullah, Mohammed</creatorcontrib><creatorcontrib>Kim, Kwang-Min</creatorcontrib><creatorcontrib>Tang, Hongxiang</creatorcontrib><creatorcontrib>Ashford, J. Wesson</creatorcontrib><creatorcontrib>Rajadas, Jayakumar</creatorcontrib><title>Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer’s disease treatment</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>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.</description><subject>631/45/275</subject><subject>631/92/609</subject><subject>Alzheimer's disease</subject><subject>Amyloidosis</subject><subject>Blood-brain barrier</subject><subject>Heterogeneity</subject><subject>Humanities and Social Sciences</subject><subject>Kinases</subject><subject>Larvae</subject><subject>Medical treatment</subject><subject>Methylene blue</subject><subject>multidisciplinary</subject><subject>Neurodegenerative diseases</subject><subject>Phenothiazine</subject><subject>Phosphorylation</subject><subject>Proteasomes</subject><subject>Protein folding</subject><subject>Science</subject><subject>Tau protein</subject><subject>Toxicity</subject><subject>Ubiquitin</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>BENPR</sourceid><recordid>eNplkdtqFTEUhgex2NL2wheQgFcK0-Ywp9wIQ_FQrCilXg9rJivdKTPJmGSK45X4Fr6eT2Jk180WAyEL1sf_r5U_y54yesaoaM6Dx1kUdVM8yo44LcqcC84f79WH2WkIdzSdksuCySfZIa9r2hSCHWU_2hjRLhCNs8RpElYLczQDie6rGUxcCVhFPrTX74vzT-01yydUBiIqcgMLmTcupOvXcSvQr2TCuFlHtEj6cUGinSft-G2DZkL_6_vPQJQJCAFJ9AhxQhtPsgMNY8DTh_c4-_zm9c3Fu_zq49vLi_YqH0paxFzSYmh0XZdMci0Bi15TWQKrgJdKAaoKhBT90DdAZTMoqamomFaMMw1VRcVx9mqrOy992mJI1h7GbvZmAr92Dkz3b8eaTXfr7rsyfVwpRBJ4_iDg3ZcFQ-zu3OJtmrljjZRUypLXiXqxpQbvQgpH7xwY7f4k1u0SS-yz_ZF25N98EvByC4TUsrfo9yz_U_sNYU-j1g</recordid><startdate>20161006</startdate><enddate>20161006</enddate><creator>Sun, Wenchao</creator><creator>Lee, Seongsoo</creator><creator>Huang, Xiaoran</creator><creator>Liu, Song</creator><creator>Inayathullah, Mohammed</creator><creator>Kim, Kwang-Min</creator><creator>Tang, Hongxiang</creator><creator>Ashford, J. 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Wesson ; Rajadas, Jayakumar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-904c8f775192f9ae4bf095a16a25ddaed6a393bcb8a098cd9f0361fd121fa6603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>631/45/275</topic><topic>631/92/609</topic><topic>Alzheimer's disease</topic><topic>Amyloidosis</topic><topic>Blood-brain barrier</topic><topic>Heterogeneity</topic><topic>Humanities and Social Sciences</topic><topic>Kinases</topic><topic>Larvae</topic><topic>Medical treatment</topic><topic>Methylene blue</topic><topic>multidisciplinary</topic><topic>Neurodegenerative diseases</topic><topic>Phenothiazine</topic><topic>Phosphorylation</topic><topic>Proteasomes</topic><topic>Protein folding</topic><topic>Science</topic><topic>Tau protein</topic><topic>Toxicity</topic><topic>Ubiquitin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Wenchao</creatorcontrib><creatorcontrib>Lee, Seongsoo</creatorcontrib><creatorcontrib>Huang, Xiaoran</creatorcontrib><creatorcontrib>Liu, Song</creatorcontrib><creatorcontrib>Inayathullah, Mohammed</creatorcontrib><creatorcontrib>Kim, Kwang-Min</creatorcontrib><creatorcontrib>Tang, Hongxiang</creatorcontrib><creatorcontrib>Ashford, J. 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Wesson</au><au>Rajadas, Jayakumar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer’s disease treatment</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-10-06</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>34784</spage><pages>34784-</pages><artnum>34784</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27708431</pmid><doi>10.1038/srep34784</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 631/45/275 631/92/609 Alzheimer's disease Amyloidosis Blood-brain barrier Heterogeneity Humanities and Social Sciences Kinases Larvae Medical treatment Methylene blue multidisciplinary Neurodegenerative diseases Phenothiazine Phosphorylation Proteasomes Protein folding Science Tau protein Toxicity Ubiquitin |
| title | Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer’s disease treatment |
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