Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease
The accumulation of intracellular β amyloid (Aβ) may be one of the factors leading to neuronal cell death in Alzheimer's disease (AD). Using a pyrazole called CNB-001, which was selected for its ability to reduce intracellular Aβ, we show that the activation of the eIF2α/ATF4 arm of the unfolde...
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| Veröffentlicht in: | The Journal of neuroscience 2013-06, Vol.33 (25), p.10512-10525 |
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| creator | Valera, Elvira Dargusch, Richard Maher, Pamela A Schubert, David |
| description | The accumulation of intracellular β amyloid (Aβ) may be one of the factors leading to neuronal cell death in Alzheimer's disease (AD). Using a pyrazole called CNB-001, which was selected for its ability to reduce intracellular Aβ, we show that the activation of the eIF2α/ATF4 arm of the unfolded protein response is sufficient to degrade aggregated intracellular Aβ. CNB-001 is a potent inhibitor of 5-lipoxygenase (5-LOX), decreases 5-LOX expression, and increases proteasome activity. 5-LOX inhibition induces eIF2α and PERK (protein kinase R-like extracellular signal-regulated kinase) phosphorylation, and HSP90 and ATF4 levels. When fed to AD transgenic mice, CNB-001 also increases eIF2α phosphorylation and HSP90 and ATF4 levels, and limits the accumulation of soluble Aβ and ubiquitinated aggregated proteins. Finally, CNB-001 maintains the expression of synapse-associated proteins and improves memory. Therefore, 5-LOX metabolism is a key element in the promotion of endoplasmic reticulum dysfunction, and its inhibition under conditions of stress is sufficient to reduce proteotoxicity both in vivo and in vitro. |
| doi_str_mv | 10.1523/JNEUROSCI.5183-12.2013 |
| format | Article |
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Using a pyrazole called CNB-001, which was selected for its ability to reduce intracellular Aβ, we show that the activation of the eIF2α/ATF4 arm of the unfolded protein response is sufficient to degrade aggregated intracellular Aβ. CNB-001 is a potent inhibitor of 5-lipoxygenase (5-LOX), decreases 5-LOX expression, and increases proteasome activity. 5-LOX inhibition induces eIF2α and PERK (protein kinase R-like extracellular signal-regulated kinase) phosphorylation, and HSP90 and ATF4 levels. When fed to AD transgenic mice, CNB-001 also increases eIF2α phosphorylation and HSP90 and ATF4 levels, and limits the accumulation of soluble Aβ and ubiquitinated aggregated proteins. Finally, CNB-001 maintains the expression of synapse-associated proteins and improves memory. 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Therefore, 5-LOX metabolism is a key element in the promotion of endoplasmic reticulum dysfunction, and its inhibition under conditions of stress is sufficient to reduce proteotoxicity both in vivo and in vitro.</description><subject>Activating Transcription Factor 4 - metabolism</subject><subject>Alzheimer Disease - enzymology</subject><subject>Alzheimer Disease - psychology</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Amyloid beta-Peptides - toxicity</subject><subject>Animals</subject><subject>Apomorphine - pharmacology</subject><subject>Arachidonate 5-Lipoxygenase - metabolism</subject><subject>Behavior, Animal - physiology</subject><subject>Blotting, Western</subject><subject>Curcumin - analogs & derivatives</subject><subject>Curcumin - pharmacology</subject><subject>Dopamine Agonists - pharmacology</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>Eukaryotic Initiation Factor-2 - metabolism</subject><subject>Humans</subject><subject>Lipoxygenase Inhibitors - pharmacology</subject><subject>Maze Learning - physiology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Peptide Fragments - metabolism</subject><subject>Phosphorylation</subject><subject>Proteasome Endopeptidase Complex - genetics</subject><subject>Protein Folding</subject><subject>Pyrazoles - pharmacology</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>Ubiquitin - metabolism</subject><issn>0270-6474</issn><issn>1529-2401</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUV1PwjAUbYxGEP0LZG_6MuzHuo4XE0NAMSiJynPTrbdQs61zHQb89Y6ARJ_uTc7HvTkHoT7BA8Ipu316GS9e52-j6YCThIWEDigm7AR1W3QY0giTU9TFVOAwjkTUQRfef2CMBSbiHHUoEwknMeuiybPT61w11pWBMwEPc1u5zXYJpfIQ2DKoateAa9zGZrbZBqrUwX3-vQJbQH3tA209tMxLdGZU7uHqMHtoMRm_jx7D2fxhOrqfhRknrAlZihNtaKpEAnooQLFsaHDEqYlMHBsTU8g01gwMyyCN2j1NgCgdCcUFTgXrobu9b7VOC9AZlE2tclnVtlD1Vjpl5X-ktCu5dF-SxQlPItIa3BwMave5Bt_IwvoM8lyV4NZeEr7LheAYt9R4T81q530N5niGYLkrQR5LkLsSJKFyV0Ir7P998ij7TZ39ABI8hrc</recordid><startdate>20130619</startdate><enddate>20130619</enddate><creator>Valera, Elvira</creator><creator>Dargusch, Richard</creator><creator>Maher, Pamela A</creator><creator>Schubert, David</creator><general>Society for Neuroscience</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>7TK</scope><scope>5PM</scope></search><sort><creationdate>20130619</creationdate><title>Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease</title><author>Valera, Elvira ; Dargusch, Richard ; Maher, Pamela A ; Schubert, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-3b08df2ba78ed97ea3c9f0452f4f66ff62ecd0d3ef3ceb4cd0b8e1ad47a570b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Activating Transcription Factor 4 - metabolism</topic><topic>Alzheimer Disease - enzymology</topic><topic>Alzheimer Disease - psychology</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Amyloid beta-Peptides - toxicity</topic><topic>Animals</topic><topic>Apomorphine - pharmacology</topic><topic>Arachidonate 5-Lipoxygenase - metabolism</topic><topic>Behavior, Animal - physiology</topic><topic>Blotting, Western</topic><topic>Curcumin - analogs & derivatives</topic><topic>Curcumin - pharmacology</topic><topic>Dopamine Agonists - pharmacology</topic><topic>Electrophoresis, Polyacrylamide Gel</topic><topic>Eukaryotic Initiation Factor-2 - metabolism</topic><topic>Humans</topic><topic>Lipoxygenase Inhibitors - pharmacology</topic><topic>Maze Learning - physiology</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Peptide Fragments - metabolism</topic><topic>Phosphorylation</topic><topic>Proteasome Endopeptidase Complex - genetics</topic><topic>Protein Folding</topic><topic>Pyrazoles - pharmacology</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>Ubiquitin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Valera, Elvira</creatorcontrib><creatorcontrib>Dargusch, Richard</creatorcontrib><creatorcontrib>Maher, Pamela A</creatorcontrib><creatorcontrib>Schubert, David</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Valera, Elvira</au><au>Dargusch, Richard</au><au>Maher, Pamela A</au><au>Schubert, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2013-06-19</date><risdate>2013</risdate><volume>33</volume><issue>25</issue><spage>10512</spage><epage>10525</epage><pages>10512-10525</pages><issn>0270-6474</issn><issn>1529-2401</issn><eissn>1529-2401</eissn><abstract>The accumulation of intracellular β amyloid (Aβ) may be one of the factors leading to neuronal cell death in Alzheimer's disease (AD). Using a pyrazole called CNB-001, which was selected for its ability to reduce intracellular Aβ, we show that the activation of the eIF2α/ATF4 arm of the unfolded protein response is sufficient to degrade aggregated intracellular Aβ. CNB-001 is a potent inhibitor of 5-lipoxygenase (5-LOX), decreases 5-LOX expression, and increases proteasome activity. 5-LOX inhibition induces eIF2α and PERK (protein kinase R-like extracellular signal-regulated kinase) phosphorylation, and HSP90 and ATF4 levels. When fed to AD transgenic mice, CNB-001 also increases eIF2α phosphorylation and HSP90 and ATF4 levels, and limits the accumulation of soluble Aβ and ubiquitinated aggregated proteins. Finally, CNB-001 maintains the expression of synapse-associated proteins and improves memory. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Activating Transcription Factor 4 - metabolism Alzheimer Disease - enzymology Alzheimer Disease - psychology Amyloid beta-Peptides - metabolism Amyloid beta-Peptides - toxicity Animals Apomorphine - pharmacology Arachidonate 5-Lipoxygenase - metabolism Behavior, Animal - physiology Blotting, Western Curcumin - analogs & derivatives Curcumin - pharmacology Dopamine Agonists - pharmacology Electrophoresis, Polyacrylamide Gel Eukaryotic Initiation Factor-2 - metabolism Humans Lipoxygenase Inhibitors - pharmacology Maze Learning - physiology Mice Mice, Transgenic Peptide Fragments - metabolism Phosphorylation Proteasome Endopeptidase Complex - genetics Protein Folding Pyrazoles - pharmacology RNA, Messenger - biosynthesis RNA, Messenger - genetics Ubiquitin - metabolism |
| title | Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease |
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