Cystatin C promotes tau protein phosphorylation and causes microtubule instability by inhibiting intracellular turnover of GSK3β in neurons
In Alzheimer's disease (AD) tau protein hyperphosphorylation causes neurofibrillary tangle formation, microtubule instability and neurodegeneration. Determining the mechanism of tau hyperphosphorylation will provide a better understanding of AD pathology. Cystatin C (CysC) is a risk factor for...
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| Veröffentlicht in: | Molecular and cellular neuroscience 2018-06, Vol.89, p.1-8 |
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| creator | Duan, Jinhai Marcellus, Kristen A. Qin, Xike Wang, Yunling Paudel, Hemant K. |
| description | In Alzheimer's disease (AD) tau protein hyperphosphorylation causes neurofibrillary tangle formation, microtubule instability and neurodegeneration. Determining the mechanism of tau hyperphosphorylation will provide a better understanding of AD pathology. Cystatin C (CysC) is a risk factor for late-onset AD and its level is upregulated in the brains of AD patients. The role of CysC is AD pathogenesis is not known. In this study, we found that CysC level is upregulated in 3xTg-AD mouse brain. We demonstrate that CysC does not affect cellular Aβ production. However, when overexpressed in neuron (NGF-differentiated PC12 cells), CysC inhibits turnover of GSK3β, promotes GSK3β-catalyzed tau phosphorylation at Ser396/404 and causes microtubule instability. Our data provide a novel insight into the role of CysC in AD pathogenesis.
•Cystatin C is one of the risk factors for LOAD.•Cystatin C does not affect Aβ production in HEK-293 cells.•Cystatin C promotes GSK3β-catalyzed tau protein phosphorylation in neurons.•Cystatin C inhibits cellular degradation of GSK3β. |
| doi_str_mv | 10.1016/j.mcn.2018.03.009 |
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•Cystatin C is one of the risk factors for LOAD.•Cystatin C does not affect Aβ production in HEK-293 cells.•Cystatin C promotes GSK3β-catalyzed tau protein phosphorylation in neurons.•Cystatin C inhibits cellular degradation of GSK3β.</description><identifier>ISSN: 1044-7431</identifier><identifier>EISSN: 1095-9327</identifier><identifier>DOI: 10.1016/j.mcn.2018.03.009</identifier><identifier>PMID: 29577984</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>3xTg-AD mice ; Alzheimer Disease - metabolism ; Alzheimer's disease ; Animals ; Cystatin C ; Cystatin C - pharmacology ; Glycogen Synthase Kinase 3 beta - metabolism ; GSK3β ; HEK293 Cells ; Humans ; Mice ; Microtubules - drug effects ; Microtubules - metabolism ; Neurons - drug effects ; Neurons - metabolism ; PC12 Cells ; Phosphorylation ; Protein Processing, Post-Translational ; Proteolysis ; Rats ; Tau phosphorylation ; tau Proteins - metabolism</subject><ispartof>Molecular and cellular neuroscience, 2018-06, Vol.89, p.1-8</ispartof><rights>2018 Elsevier Inc.</rights><rights>Copyright © 2018 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c379t-825c91ded47876e17ddc3c0ac64aceed1f7c10e50866fe57c99a9a92d64880223</citedby><cites>FETCH-LOGICAL-c379t-825c91ded47876e17ddc3c0ac64aceed1f7c10e50866fe57c99a9a92d64880223</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.mcn.2018.03.009$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29577984$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duan, Jinhai</creatorcontrib><creatorcontrib>Marcellus, Kristen A.</creatorcontrib><creatorcontrib>Qin, Xike</creatorcontrib><creatorcontrib>Wang, Yunling</creatorcontrib><creatorcontrib>Paudel, Hemant K.</creatorcontrib><title>Cystatin C promotes tau protein phosphorylation and causes microtubule instability by inhibiting intracellular turnover of GSK3β in neurons</title><title>Molecular and cellular neuroscience</title><addtitle>Mol Cell Neurosci</addtitle><description>In Alzheimer's disease (AD) tau protein hyperphosphorylation causes neurofibrillary tangle formation, microtubule instability and neurodegeneration. Determining the mechanism of tau hyperphosphorylation will provide a better understanding of AD pathology. Cystatin C (CysC) is a risk factor for late-onset AD and its level is upregulated in the brains of AD patients. The role of CysC is AD pathogenesis is not known. In this study, we found that CysC level is upregulated in 3xTg-AD mouse brain. We demonstrate that CysC does not affect cellular Aβ production. However, when overexpressed in neuron (NGF-differentiated PC12 cells), CysC inhibits turnover of GSK3β, promotes GSK3β-catalyzed tau phosphorylation at Ser396/404 and causes microtubule instability. Our data provide a novel insight into the role of CysC in AD pathogenesis.
•Cystatin C is one of the risk factors for LOAD.•Cystatin C does not affect Aβ production in HEK-293 cells.•Cystatin C promotes GSK3β-catalyzed tau protein phosphorylation in neurons.•Cystatin C inhibits cellular degradation of GSK3β.</description><subject>3xTg-AD mice</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer's disease</subject><subject>Animals</subject><subject>Cystatin C</subject><subject>Cystatin C - pharmacology</subject><subject>Glycogen Synthase Kinase 3 beta - metabolism</subject><subject>GSK3β</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mice</subject><subject>Microtubules - drug effects</subject><subject>Microtubules - metabolism</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>PC12 Cells</subject><subject>Phosphorylation</subject><subject>Protein Processing, Post-Translational</subject><subject>Proteolysis</subject><subject>Rats</subject><subject>Tau phosphorylation</subject><subject>tau Proteins - metabolism</subject><issn>1044-7431</issn><issn>1095-9327</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU2O1DAQhSMEYoaBA7BBXrJJsJ3EjsUKtWBAjMQCWFuOXWHcSpzGPyPlDpyGg3AmKvTAElmWq6zvPbuqquo5ow2jTLw6NosNDadsaGjbUKoeVJeMqr5WLZcP97jratm17KJ6ktKRUtpz1T6uLrjqpVRDd1n9OGwpm-wDOZBTXJc1QyLZlD3JgNen2zXhjtuM1BqICY5YUxJii7cIlbHMQHxAm9HPPm9k3DC99aNH228Y5mgszHOZTSS5xLDeQSTrRK4_f2x__USABChxDelp9Wgyc4Jn9-dV9fXd2y-H9_XNp-sPhzc3tW2lyvXAe6uYA9fJQQpg0jnbWmqs6PAhcGySllHo6SDEBL20Shlc3IluGCjn7VX18uyLRX4vkLJefNq_aAKsJem9o0IIyhmi7IxiqSlFmPQp-sXETTOq9yHoo8Yh_JFo2mocAmpe3NuXcQH3T_G36wi8PgOARd55iDpZD8GC8xFs1m71_7H_DeF1nFE</recordid><startdate>20180601</startdate><enddate>20180601</enddate><creator>Duan, Jinhai</creator><creator>Marcellus, Kristen A.</creator><creator>Qin, Xike</creator><creator>Wang, Yunling</creator><creator>Paudel, Hemant K.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20180601</creationdate><title>Cystatin C promotes tau protein phosphorylation and causes microtubule instability by inhibiting intracellular turnover of GSK3β in neurons</title><author>Duan, Jinhai ; Marcellus, Kristen A. ; Qin, Xike ; Wang, Yunling ; Paudel, Hemant K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c379t-825c91ded47876e17ddc3c0ac64aceed1f7c10e50866fe57c99a9a92d64880223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>3xTg-AD mice</topic><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer's disease</topic><topic>Animals</topic><topic>Cystatin C</topic><topic>Cystatin C - pharmacology</topic><topic>Glycogen Synthase Kinase 3 beta - metabolism</topic><topic>GSK3β</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mice</topic><topic>Microtubules - drug effects</topic><topic>Microtubules - metabolism</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>PC12 Cells</topic><topic>Phosphorylation</topic><topic>Protein Processing, Post-Translational</topic><topic>Proteolysis</topic><topic>Rats</topic><topic>Tau phosphorylation</topic><topic>tau Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Duan, Jinhai</creatorcontrib><creatorcontrib>Marcellus, Kristen A.</creatorcontrib><creatorcontrib>Qin, Xike</creatorcontrib><creatorcontrib>Wang, Yunling</creatorcontrib><creatorcontrib>Paudel, Hemant K.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular and cellular neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Duan, Jinhai</au><au>Marcellus, Kristen A.</au><au>Qin, Xike</au><au>Wang, Yunling</au><au>Paudel, Hemant K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cystatin C promotes tau protein phosphorylation and causes microtubule instability by inhibiting intracellular turnover of GSK3β in neurons</atitle><jtitle>Molecular and cellular neuroscience</jtitle><addtitle>Mol Cell Neurosci</addtitle><date>2018-06-01</date><risdate>2018</risdate><volume>89</volume><spage>1</spage><epage>8</epage><pages>1-8</pages><issn>1044-7431</issn><eissn>1095-9327</eissn><abstract>In Alzheimer's disease (AD) tau protein hyperphosphorylation causes neurofibrillary tangle formation, microtubule instability and neurodegeneration. Determining the mechanism of tau hyperphosphorylation will provide a better understanding of AD pathology. Cystatin C (CysC) is a risk factor for late-onset AD and its level is upregulated in the brains of AD patients. The role of CysC is AD pathogenesis is not known. In this study, we found that CysC level is upregulated in 3xTg-AD mouse brain. We demonstrate that CysC does not affect cellular Aβ production. However, when overexpressed in neuron (NGF-differentiated PC12 cells), CysC inhibits turnover of GSK3β, promotes GSK3β-catalyzed tau phosphorylation at Ser396/404 and causes microtubule instability. Our data provide a novel insight into the role of CysC in AD pathogenesis.
•Cystatin C is one of the risk factors for LOAD.•Cystatin C does not affect Aβ production in HEK-293 cells.•Cystatin C promotes GSK3β-catalyzed tau protein phosphorylation in neurons.•Cystatin C inhibits cellular degradation of GSK3β.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29577984</pmid><doi>10.1016/j.mcn.2018.03.009</doi><tpages>8</tpages></addata></record> |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | 3xTg-AD mice Alzheimer Disease - metabolism Alzheimer's disease Animals Cystatin C Cystatin C - pharmacology Glycogen Synthase Kinase 3 beta - metabolism GSK3β HEK293 Cells Humans Mice Microtubules - drug effects Microtubules - metabolism Neurons - drug effects Neurons - metabolism PC12 Cells Phosphorylation Protein Processing, Post-Translational Proteolysis Rats Tau phosphorylation tau Proteins - metabolism |
| title | Cystatin C promotes tau protein phosphorylation and causes microtubule instability by inhibiting intracellular turnover of GSK3β in neurons |
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