A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease
The immunoproteasome (iP) is a variant of the constitutive proteasome (cP) that is abundantly expressed in immune cells which can also be induced in somatic cells by cytokines such as TNF-α or IFN-γ. Accumulating evidence support that the iP is closely linked to multiple facets of inflammatory respo...
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| Veröffentlicht in: | Scientific reports 2019-12, Vol.9 (1), p.18393-13, Article 18393 |
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| creator | Yeo, In Jun Lee, Min Jae Baek, Ahruem Miller, Zachary Bhattarai, Deepak Baek, Yu Mi Jeong, Hyun Jung Kim, Yun Kyung Kim, Dong-Eun Hong, Jin Tae Kim, Kyung Bo |
| description | The immunoproteasome (iP) is a variant of the constitutive proteasome (cP) that is abundantly expressed in immune cells which can also be induced in somatic cells by cytokines such as TNF-α or IFN-γ. Accumulating evidence support that the iP is closely linked to multiple facets of inflammatory response, eventually leading to the development of several iP inhibitors as potential therapeutic agents for autoimmune diseases. Recent studies also found that the iP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients, but the role it plays in the pathogenesis of AD remains unclear. In this study, we investigated the effects of several proteasome inhibitors on cognitive function in AD mouse models and found that YU102, a dual inhibitor of the iP catalytic subunit LMP2 and the cP catalytic subunit Y, ameliorates cognitive impairments in AD mouse models without affecting Aβ deposition. The data obtained from our investigation revealed that YU102 suppresses the secretion of inflammatory cytokines from microglial cells. Overall, this study indicates that there may exist a potential link between LMP2/Y and microglia-mediated neuroinflammation and that inhibition of these subunits may offer a new therapeutic strategy for AD. |
| doi_str_mv | 10.1038/s41598-019-54846-z |
| format | Article |
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Accumulating evidence support that the iP is closely linked to multiple facets of inflammatory response, eventually leading to the development of several iP inhibitors as potential therapeutic agents for autoimmune diseases. Recent studies also found that the iP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients, but the role it plays in the pathogenesis of AD remains unclear. In this study, we investigated the effects of several proteasome inhibitors on cognitive function in AD mouse models and found that YU102, a dual inhibitor of the iP catalytic subunit LMP2 and the cP catalytic subunit Y, ameliorates cognitive impairments in AD mouse models without affecting Aβ deposition. The data obtained from our investigation revealed that YU102 suppresses the secretion of inflammatory cytokines from microglial cells. Overall, this study indicates that there may exist a potential link between LMP2/Y and microglia-mediated neuroinflammation and that inhibition of these subunits may offer a new therapeutic strategy for AD.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-54846-z</identifier><identifier>PMID: 31804556</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154 ; 631/92 ; Alzheimer Disease - drug therapy ; Alzheimer Disease - enzymology ; Alzheimer Disease - genetics ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid ; Amyloid beta-Peptides - genetics ; Amyloid beta-Peptides - metabolism ; Animal models ; Animals ; Autoimmune diseases ; Brain - drug effects ; Brain - enzymology ; Brain - pathology ; Catalytic subunits ; Cell Line ; Cognitive ability ; Cognitive Dysfunction - drug therapy ; Cognitive Dysfunction - enzymology ; Cognitive Dysfunction - genetics ; Cognitive Dysfunction - pathology ; Cysteine Endopeptidases - genetics ; Cysteine Endopeptidases - metabolism ; Cytokines ; Disease ; Disease Models, Animal ; Gene Expression Regulation ; Glial cells ; Humanities and Social Sciences ; Humans ; Inflammation ; Interleukin-1alpha - genetics ; Interleukin-1alpha - metabolism ; Interleukin-6 - genetics ; Interleukin-6 - metabolism ; Liver - drug effects ; Liver - enzymology ; Liver - pathology ; Maze Learning - drug effects ; Mice ; Mice, Inbred ICR ; Mice, Transgenic ; Microglia ; Monocyte Chemoattractant Proteins - genetics ; Monocyte Chemoattractant Proteins - metabolism ; multidisciplinary ; Neuroglia - drug effects ; Neuroglia - enzymology ; Neuroglia - pathology ; Proteasome inhibitors ; Proteasome Inhibitors - pharmacology ; Protein Subunits - antagonists & inhibitors ; Protein Subunits - genetics ; Protein Subunits - metabolism ; Science ; Science (multidisciplinary) ; Somatic cells ; Spleen - drug effects ; Spleen - enzymology ; Spleen - pathology ; Tumor necrosis factor-α ; γ-Interferon</subject><ispartof>Scientific reports, 2019-12, Vol.9 (1), p.18393-13, Article 18393</ispartof><rights>The Author(s) 2019</rights><rights>2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-230a8459145fc50f8aeea680ec77b9b29f93f4caf0e59bcf99202d8bb24f2a023</citedby><cites>FETCH-LOGICAL-c474t-230a8459145fc50f8aeea680ec77b9b29f93f4caf0e59bcf99202d8bb24f2a023</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/PMC6895163/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895163/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31804556$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yeo, In Jun</creatorcontrib><creatorcontrib>Lee, Min Jae</creatorcontrib><creatorcontrib>Baek, Ahruem</creatorcontrib><creatorcontrib>Miller, Zachary</creatorcontrib><creatorcontrib>Bhattarai, Deepak</creatorcontrib><creatorcontrib>Baek, Yu Mi</creatorcontrib><creatorcontrib>Jeong, Hyun Jung</creatorcontrib><creatorcontrib>Kim, Yun Kyung</creatorcontrib><creatorcontrib>Kim, Dong-Eun</creatorcontrib><creatorcontrib>Hong, Jin Tae</creatorcontrib><creatorcontrib>Kim, Kyung Bo</creatorcontrib><title>A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The immunoproteasome (iP) is a variant of the constitutive proteasome (cP) that is abundantly expressed in immune cells which can also be induced in somatic cells by cytokines such as TNF-α or IFN-γ. Accumulating evidence support that the iP is closely linked to multiple facets of inflammatory response, eventually leading to the development of several iP inhibitors as potential therapeutic agents for autoimmune diseases. Recent studies also found that the iP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients, but the role it plays in the pathogenesis of AD remains unclear. In this study, we investigated the effects of several proteasome inhibitors on cognitive function in AD mouse models and found that YU102, a dual inhibitor of the iP catalytic subunit LMP2 and the cP catalytic subunit Y, ameliorates cognitive impairments in AD mouse models without affecting Aβ deposition. The data obtained from our investigation revealed that YU102 suppresses the secretion of inflammatory cytokines from microglial cells. Overall, this study indicates that there may exist a potential link between LMP2/Y and microglia-mediated neuroinflammation and that inhibition of these subunits may offer a new therapeutic strategy for AD.</description><subject>631/154</subject><subject>631/92</subject><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - enzymology</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid</subject><subject>Amyloid beta-Peptides - genetics</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animal models</subject><subject>Animals</subject><subject>Autoimmune diseases</subject><subject>Brain - drug effects</subject><subject>Brain - enzymology</subject><subject>Brain - pathology</subject><subject>Catalytic subunits</subject><subject>Cell Line</subject><subject>Cognitive ability</subject><subject>Cognitive Dysfunction - drug therapy</subject><subject>Cognitive Dysfunction - enzymology</subject><subject>Cognitive Dysfunction - genetics</subject><subject>Cognitive Dysfunction - pathology</subject><subject>Cysteine Endopeptidases - genetics</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>Cytokines</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Gene Expression Regulation</subject><subject>Glial cells</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Interleukin-1alpha - genetics</subject><subject>Interleukin-1alpha - metabolism</subject><subject>Interleukin-6 - genetics</subject><subject>Interleukin-6 - metabolism</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - pathology</subject><subject>Maze Learning - drug effects</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Mice, Transgenic</subject><subject>Microglia</subject><subject>Monocyte Chemoattractant Proteins - genetics</subject><subject>Monocyte Chemoattractant Proteins - metabolism</subject><subject>multidisciplinary</subject><subject>Neuroglia - drug effects</subject><subject>Neuroglia - enzymology</subject><subject>Neuroglia - pathology</subject><subject>Proteasome inhibitors</subject><subject>Proteasome Inhibitors - pharmacology</subject><subject>Protein Subunits - antagonists & inhibitors</subject><subject>Protein Subunits - genetics</subject><subject>Protein Subunits - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Somatic cells</subject><subject>Spleen - drug effects</subject><subject>Spleen - enzymology</subject><subject>Spleen - pathology</subject><subject>Tumor necrosis factor-α</subject><subject>γ-Interferon</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kc1uEzEUhUcIRKvSF2CBLLFhM-DfxN4gRRUUpCBYwIKV5fFcJ65m7GB7KjUrlrxCX48nwWlCKCyYjUe-3zn28WmapwS_JJjJV5kToWSLiWoFl3zWbh80pxRz0VJG6cN7_yfNec5XuH6CKk7U4-aEEVmnYnba_FigfjID8mHtO19iQtGhsga0SbGAyXEEZE0xw03xFuWpm4IvGS0_fKLIhB59RaYUCJMpkFHvc5XcaVcJcvYxVGM0xqlujrGHIe_sF8N2DX6E9PP77VH0pHnkzJDh_LCeNV_evvl88a5dfrx8f7FYtpbPeamBsJFcKMKFswI7aQDMTGKw83mnOqqcYo5b4zAI1VmnFMW0l11HuaMGU3bWvN77bqZuhN5CKMkMepP8aNKNjsbrvyfBr_UqXuuZVILMWDV4cTBI8dsEuejRZwvDYALUoHr35ITNJduhz_9Br-KUQo13oBiXuFJ0T9kUc07gjpchWO-61vuude1a33Wtt1X07H6Mo-R3sxVgeyDXUVhB-nP2f2x_AcqKuRg</recordid><startdate>20191205</startdate><enddate>20191205</enddate><creator>Yeo, In Jun</creator><creator>Lee, Min Jae</creator><creator>Baek, Ahruem</creator><creator>Miller, Zachary</creator><creator>Bhattarai, Deepak</creator><creator>Baek, Yu Mi</creator><creator>Jeong, Hyun Jung</creator><creator>Kim, Yun Kyung</creator><creator>Kim, Dong-Eun</creator><creator>Hong, Jin Tae</creator><creator>Kim, Kyung Bo</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20191205</creationdate><title>A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease</title><author>Yeo, In Jun ; Lee, Min Jae ; Baek, Ahruem ; Miller, Zachary ; Bhattarai, Deepak ; Baek, Yu Mi ; Jeong, Hyun Jung ; Kim, Yun Kyung ; Kim, Dong-Eun ; Hong, Jin Tae ; Kim, Kyung Bo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-230a8459145fc50f8aeea680ec77b9b29f93f4caf0e59bcf99202d8bb24f2a023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>631/154</topic><topic>631/92</topic><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - enzymology</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid</topic><topic>Amyloid beta-Peptides - genetics</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Animal models</topic><topic>Animals</topic><topic>Autoimmune diseases</topic><topic>Brain - drug effects</topic><topic>Brain - enzymology</topic><topic>Brain - pathology</topic><topic>Catalytic subunits</topic><topic>Cell Line</topic><topic>Cognitive ability</topic><topic>Cognitive Dysfunction - drug therapy</topic><topic>Cognitive Dysfunction - enzymology</topic><topic>Cognitive Dysfunction - genetics</topic><topic>Cognitive Dysfunction - pathology</topic><topic>Cysteine Endopeptidases - genetics</topic><topic>Cysteine Endopeptidases - metabolism</topic><topic>Cytokines</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>Gene Expression Regulation</topic><topic>Glial cells</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Interleukin-1alpha - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yeo, In Jun</au><au>Lee, Min Jae</au><au>Baek, Ahruem</au><au>Miller, Zachary</au><au>Bhattarai, Deepak</au><au>Baek, Yu Mi</au><au>Jeong, Hyun Jung</au><au>Kim, Yun Kyung</au><au>Kim, Dong-Eun</au><au>Hong, Jin Tae</au><au>Kim, Kyung Bo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2019-12-05</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>18393</spage><epage>13</epage><pages>18393-13</pages><artnum>18393</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The immunoproteasome (iP) is a variant of the constitutive proteasome (cP) that is abundantly expressed in immune cells which can also be induced in somatic cells by cytokines such as TNF-α or IFN-γ. Accumulating evidence support that the iP is closely linked to multiple facets of inflammatory response, eventually leading to the development of several iP inhibitors as potential therapeutic agents for autoimmune diseases. Recent studies also found that the iP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients, but the role it plays in the pathogenesis of AD remains unclear. In this study, we investigated the effects of several proteasome inhibitors on cognitive function in AD mouse models and found that YU102, a dual inhibitor of the iP catalytic subunit LMP2 and the cP catalytic subunit Y, ameliorates cognitive impairments in AD mouse models without affecting Aβ deposition. The data obtained from our investigation revealed that YU102 suppresses the secretion of inflammatory cytokines from microglial cells. Overall, this study indicates that there may exist a potential link between LMP2/Y and microglia-mediated neuroinflammation and that inhibition of these subunits may offer a new therapeutic strategy for AD.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31804556</pmid><doi>10.1038/s41598-019-54846-z</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/154 631/92 Alzheimer Disease - drug therapy Alzheimer Disease - enzymology Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer's disease Amyloid Amyloid beta-Peptides - genetics Amyloid beta-Peptides - metabolism Animal models Animals Autoimmune diseases Brain - drug effects Brain - enzymology Brain - pathology Catalytic subunits Cell Line Cognitive ability Cognitive Dysfunction - drug therapy Cognitive Dysfunction - enzymology Cognitive Dysfunction - genetics Cognitive Dysfunction - pathology Cysteine Endopeptidases - genetics Cysteine Endopeptidases - metabolism Cytokines Disease Disease Models, Animal Gene Expression Regulation Glial cells Humanities and Social Sciences Humans Inflammation Interleukin-1alpha - genetics Interleukin-1alpha - metabolism Interleukin-6 - genetics Interleukin-6 - metabolism Liver - drug effects Liver - enzymology Liver - pathology Maze Learning - drug effects Mice Mice, Inbred ICR Mice, Transgenic Microglia Monocyte Chemoattractant Proteins - genetics Monocyte Chemoattractant Proteins - metabolism multidisciplinary Neuroglia - drug effects Neuroglia - enzymology Neuroglia - pathology Proteasome inhibitors Proteasome Inhibitors - pharmacology Protein Subunits - antagonists & inhibitors Protein Subunits - genetics Protein Subunits - metabolism Science Science (multidisciplinary) Somatic cells Spleen - drug effects Spleen - enzymology Spleen - pathology Tumor necrosis factor-α γ-Interferon |
| title | A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease |
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