The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis
Abstract Here we employed human SHEP neuroblastoma cells either stably or inducibly expressing the amyloid precursor protein (APP) intracellular domain (AICD) to investigate its ability to modulate stress-induced cell death. Analysis of effector caspase activation revealed that AICD overexpression w...
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| Veröffentlicht in: | Neurobiology of aging 2012-09, Vol.33 (9), p.2200-2209 |
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| creator | Kögel, Donat Concannon, Caoimhín G Müller, Thorsten König, Hildegard Bonner, Caroline Poeschel, Simone Chang, Steffi Egensperger, Rupert Prehn, Jochen H.M |
| description | Abstract Here we employed human SHEP neuroblastoma cells either stably or inducibly expressing the amyloid precursor protein (APP) intracellular domain (AICD) to investigate its ability to modulate stress-induced cell death. Analysis of effector caspase activation revealed that AICD overexpression was specifically associated with an increased sensitivity to apoptosis induced by the 2 endoplasmic reticulum (ER) stressors thapsigargin and tunicamycin, but not by staurosporine (STS). Basal and ER stress-induced expression of Bip/Grp78 and C/EBP-homologous protein/GADD153 were not altered by AICD implying that AICD potentiated cell death downstream or independent of the conserved unfolded protein response (UPR). Interestingly, quantitative polymerase chain reaction analysis and reporter gene assays revealed that AICD significantly downregulated messenger RNA levels of the Alzheimer's disease susceptibility gene ApoJ/clusterin, indicating transcriptional repression. Knockdown of ApoJ/clusterin mimicked the effect of AICD on ER stress-induced apoptosis, but had no discernible effect on staurosporine-induced cell death. Our data suggest that altered levels of AICD may abolish the prosurvival function of ApoJ/clusterin and increase the susceptibility of neurons to ER stress-mediated cell death, a pathway that may contribute to the pathogenesis of Alzheimer's disease. |
| doi_str_mv | 10.1016/j.neurobiolaging.2011.06.012 |
| format | Article |
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Analysis of effector caspase activation revealed that AICD overexpression was specifically associated with an increased sensitivity to apoptosis induced by the 2 endoplasmic reticulum (ER) stressors thapsigargin and tunicamycin, but not by staurosporine (STS). Basal and ER stress-induced expression of Bip/Grp78 and C/EBP-homologous protein/GADD153 were not altered by AICD implying that AICD potentiated cell death downstream or independent of the conserved unfolded protein response (UPR). Interestingly, quantitative polymerase chain reaction analysis and reporter gene assays revealed that AICD significantly downregulated messenger RNA levels of the Alzheimer's disease susceptibility gene ApoJ/clusterin, indicating transcriptional repression. Knockdown of ApoJ/clusterin mimicked the effect of AICD on ER stress-induced apoptosis, but had no discernible effect on staurosporine-induced cell death. Our data suggest that altered levels of AICD may abolish the prosurvival function of ApoJ/clusterin and increase the susceptibility of neurons to ER stress-mediated cell death, a pathway that may contribute to the pathogenesis of Alzheimer's disease.</description><identifier>ISSN: 0197-4580</identifier><identifier>EISSN: 1558-1497</identifier><identifier>DOI: 10.1016/j.neurobiolaging.2011.06.012</identifier><identifier>PMID: 21803450</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alzheimer's disease ; Amyloid precursor protein ; Apoptosis ; Apoptosis - drug effects ; Caspases ; Cell Line, Tumor ; Clusterin - genetics ; Clusterin - metabolism ; Cytidine Deaminase - pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Endoplasmic Reticulum Stress - drug effects ; Endoplasmic Reticulum Stress - physiology ; Enzyme Inhibitors - pharmacology ; ER stress ; Flow Cytometry ; Gene Expression Regulation - drug effects ; Green Fluorescent Proteins - genetics ; Heat-Shock Proteins - genetics ; Heat-Shock Proteins - metabolism ; Humans ; Internal Medicine ; Neuroblastoma ; Neurology ; RNA, Messenger - metabolism ; Signal Transduction - drug effects ; Thapsigargin - pharmacology ; Time Factors ; Transcription ; Transfection ; Tunicamycin - pharmacology ; Unfolded protein response ; Unfolded Protein Response - drug effects</subject><ispartof>Neurobiology of aging, 2012-09, Vol.33 (9), p.2200-2209</ispartof><rights>Elsevier Inc.</rights><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-e11e475c807728d8836c45d6f54f0964dff7e6dc021de2f4fe98da00d073cce93</citedby><cites>FETCH-LOGICAL-c474t-e11e475c807728d8836c45d6f54f0964dff7e6dc021de2f4fe98da00d073cce93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neurobiolaging.2011.06.012$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3552,27931,27932,46002</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21803450$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kögel, Donat</creatorcontrib><creatorcontrib>Concannon, Caoimhín G</creatorcontrib><creatorcontrib>Müller, Thorsten</creatorcontrib><creatorcontrib>König, Hildegard</creatorcontrib><creatorcontrib>Bonner, Caroline</creatorcontrib><creatorcontrib>Poeschel, Simone</creatorcontrib><creatorcontrib>Chang, Steffi</creatorcontrib><creatorcontrib>Egensperger, Rupert</creatorcontrib><creatorcontrib>Prehn, Jochen H.M</creatorcontrib><title>The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis</title><title>Neurobiology of aging</title><addtitle>Neurobiol Aging</addtitle><description>Abstract Here we employed human SHEP neuroblastoma cells either stably or inducibly expressing the amyloid precursor protein (APP) intracellular domain (AICD) to investigate its ability to modulate stress-induced cell death. Analysis of effector caspase activation revealed that AICD overexpression was specifically associated with an increased sensitivity to apoptosis induced by the 2 endoplasmic reticulum (ER) stressors thapsigargin and tunicamycin, but not by staurosporine (STS). Basal and ER stress-induced expression of Bip/Grp78 and C/EBP-homologous protein/GADD153 were not altered by AICD implying that AICD potentiated cell death downstream or independent of the conserved unfolded protein response (UPR). Interestingly, quantitative polymerase chain reaction analysis and reporter gene assays revealed that AICD significantly downregulated messenger RNA levels of the Alzheimer's disease susceptibility gene ApoJ/clusterin, indicating transcriptional repression. Knockdown of ApoJ/clusterin mimicked the effect of AICD on ER stress-induced apoptosis, but had no discernible effect on staurosporine-induced cell death. Our data suggest that altered levels of AICD may abolish the prosurvival function of ApoJ/clusterin and increase the susceptibility of neurons to ER stress-mediated cell death, a pathway that may contribute to the pathogenesis of Alzheimer's disease.</description><subject>Alzheimer's disease</subject><subject>Amyloid precursor protein</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Caspases</subject><subject>Cell Line, Tumor</subject><subject>Clusterin - genetics</subject><subject>Clusterin - metabolism</subject><subject>Cytidine Deaminase - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Interactions</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Endoplasmic Reticulum Stress - physiology</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>ER stress</subject><subject>Flow Cytometry</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Green Fluorescent Proteins - genetics</subject><subject>Heat-Shock Proteins - genetics</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Neuroblastoma</subject><subject>Neurology</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Thapsigargin - pharmacology</subject><subject>Time Factors</subject><subject>Transcription</subject><subject>Transfection</subject><subject>Tunicamycin - pharmacology</subject><subject>Unfolded protein response</subject><subject>Unfolded Protein Response - drug effects</subject><issn>0197-4580</issn><issn>1558-1497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNksFu1DAQhi0EotvCK6AcOJRDwozjxImEkFZLC1UrUUE5W649KV6ydrATpL59E22pVC70NJdv5h99-hl7i1AgYP1-W3iaYrh2odc3zt8UHBALqAtA_oytsKqaHEUrn7MVYCtzUTVwwA5T2gKAFLJ-yQ44NlCKClbs_OonZevLy8z5MWpDfT_1OmY27LTz2fH6bPPpXTaEkfzo9EgpO_mWpTFSSrnzdjJkMz2EYQzJpVfsRaf7RK_v5xH7cXpytfmSX3z9fLZZX-RGSDHmhEhCVqYBKXljm6asjahs3VWig7YWtusk1dYAR0u8Ex21jdUAFmRpDLXlETve3x1i-D1RGtXOpeV17SlMSWHFoWxQovg_ClzMmdDKGf2wR00MKUXq1BDdTsfbGVKLebVVj82rxbyCWs3m5_U390nT9Y7sw_Jf1TNwugdoVvPHUVTJOPKzQRfJjMoG99Skj_8cMr3zzuj-F91S2oYp-lm_QpW4AvV9acFSAkQAztu6vAORqbD9</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Kögel, Donat</creator><creator>Concannon, Caoimhín G</creator><creator>Müller, Thorsten</creator><creator>König, Hildegard</creator><creator>Bonner, Caroline</creator><creator>Poeschel, Simone</creator><creator>Chang, Steffi</creator><creator>Egensperger, Rupert</creator><creator>Prehn, Jochen H.M</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><scope>7TK</scope></search><sort><creationdate>20120901</creationdate><title>The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis</title><author>Kögel, Donat ; Concannon, Caoimhín G ; Müller, Thorsten ; König, Hildegard ; Bonner, Caroline ; Poeschel, Simone ; Chang, Steffi ; Egensperger, Rupert ; Prehn, Jochen H.M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-e11e475c807728d8836c45d6f54f0964dff7e6dc021de2f4fe98da00d073cce93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Alzheimer's disease</topic><topic>Amyloid precursor protein</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Caspases</topic><topic>Cell Line, Tumor</topic><topic>Clusterin - genetics</topic><topic>Clusterin - metabolism</topic><topic>Cytidine Deaminase - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Interactions</topic><topic>Endoplasmic Reticulum Stress - drug effects</topic><topic>Endoplasmic Reticulum Stress - physiology</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>ER stress</topic><topic>Flow Cytometry</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Green Fluorescent Proteins - genetics</topic><topic>Heat-Shock Proteins - genetics</topic><topic>Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Neuroblastoma</topic><topic>Neurology</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Thapsigargin - pharmacology</topic><topic>Time Factors</topic><topic>Transcription</topic><topic>Transfection</topic><topic>Tunicamycin - pharmacology</topic><topic>Unfolded protein response</topic><topic>Unfolded Protein Response - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kögel, Donat</creatorcontrib><creatorcontrib>Concannon, Caoimhín G</creatorcontrib><creatorcontrib>Müller, Thorsten</creatorcontrib><creatorcontrib>König, Hildegard</creatorcontrib><creatorcontrib>Bonner, Caroline</creatorcontrib><creatorcontrib>Poeschel, Simone</creatorcontrib><creatorcontrib>Chang, Steffi</creatorcontrib><creatorcontrib>Egensperger, Rupert</creatorcontrib><creatorcontrib>Prehn, Jochen H.M</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><collection>Neurosciences Abstracts</collection><jtitle>Neurobiology of aging</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kögel, Donat</au><au>Concannon, Caoimhín G</au><au>Müller, Thorsten</au><au>König, Hildegard</au><au>Bonner, Caroline</au><au>Poeschel, Simone</au><au>Chang, Steffi</au><au>Egensperger, Rupert</au><au>Prehn, Jochen H.M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis</atitle><jtitle>Neurobiology of aging</jtitle><addtitle>Neurobiol Aging</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>33</volume><issue>9</issue><spage>2200</spage><epage>2209</epage><pages>2200-2209</pages><issn>0197-4580</issn><eissn>1558-1497</eissn><abstract>Abstract Here we employed human SHEP neuroblastoma cells either stably or inducibly expressing the amyloid precursor protein (APP) intracellular domain (AICD) to investigate its ability to modulate stress-induced cell death. Analysis of effector caspase activation revealed that AICD overexpression was specifically associated with an increased sensitivity to apoptosis induced by the 2 endoplasmic reticulum (ER) stressors thapsigargin and tunicamycin, but not by staurosporine (STS). Basal and ER stress-induced expression of Bip/Grp78 and C/EBP-homologous protein/GADD153 were not altered by AICD implying that AICD potentiated cell death downstream or independent of the conserved unfolded protein response (UPR). Interestingly, quantitative polymerase chain reaction analysis and reporter gene assays revealed that AICD significantly downregulated messenger RNA levels of the Alzheimer's disease susceptibility gene ApoJ/clusterin, indicating transcriptional repression. Knockdown of ApoJ/clusterin mimicked the effect of AICD on ER stress-induced apoptosis, but had no discernible effect on staurosporine-induced cell death. Our data suggest that altered levels of AICD may abolish the prosurvival function of ApoJ/clusterin and increase the susceptibility of neurons to ER stress-mediated cell death, a pathway that may contribute to the pathogenesis of Alzheimer's disease.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21803450</pmid><doi>10.1016/j.neurobiolaging.2011.06.012</doi><tpages>10</tpages></addata></record> |
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| subjects | Alzheimer's disease Amyloid precursor protein Apoptosis Apoptosis - drug effects Caspases Cell Line, Tumor Clusterin - genetics Clusterin - metabolism Cytidine Deaminase - pharmacology Dose-Response Relationship, Drug Drug Interactions Endoplasmic Reticulum Stress - drug effects Endoplasmic Reticulum Stress - physiology Enzyme Inhibitors - pharmacology ER stress Flow Cytometry Gene Expression Regulation - drug effects Green Fluorescent Proteins - genetics Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism Humans Internal Medicine Neuroblastoma Neurology RNA, Messenger - metabolism Signal Transduction - drug effects Thapsigargin - pharmacology Time Factors Transcription Transfection Tunicamycin - pharmacology Unfolded protein response Unfolded Protein Response - drug effects |
| title | The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis |
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