Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells
A hallmark of Alzheimer’s disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively re...
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creator | Ting, Lai-Lei Lu, Hsien-Tsung Yen, Shu-Fen Ngo, Thi Huong Tu, Fang-Yu Tsai, I-Shih Tsai, Yi-Hua Chang, Fu-Yen Li, Xiao-Jiang Li, Shihua Lee, Ching-Kuo Kao, Shu-Huei Kuo, Yu-Min Lin, Yung-Feng |
description | A hallmark of Alzheimer’s disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as
Ahi1-
knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation. |
doi_str_mv | 10.1007/s12035-019-1587-1 |
format | Article |
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Ahi1-
knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.</description><identifier>ISSN: 0893-7648</identifier><identifier>EISSN: 1559-1182</identifier><identifier>DOI: 10.1007/s12035-019-1587-1</identifier><identifier>PMID: 31062249</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Adaptor Proteins, Vesicular Transport - metabolism ; Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid - metabolism ; Amyloid beta-Protein Precursor - metabolism ; Amyloid precursor protein ; Amyloidogenesis ; Animals ; Axonogenesis ; Biomedical and Life Sciences ; Biomedicine ; Brain ; Cell Biology ; Cell culture ; Cell Differentiation ; Cell Line ; Cell Survival ; Culture media ; Extracellular signal-regulated kinase ; Genotypes ; Hap1 protein ; Humans ; Huntingtin ; Lysates ; Mental disorders ; Mice, Inbred C57BL ; Models, Biological ; Nerve Growth Factors - metabolism ; Neurobiology ; Neuroblastoma ; Neurodevelopmental disorders ; Neurology ; Neuroprotection ; Neurosciences ; Pathology ; Plaques ; Protein Binding ; Translocation ; Tropomyosin</subject><ispartof>Molecular neurobiology, 2019-11, Vol.56 (11), p.7572-7582</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2019</rights><rights>Molecular Neurobiology is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-2e7fceea0e7f23232cc657252662502b4c388762eaada9b70c21890989a615d63</citedby><cites>FETCH-LOGICAL-c372t-2e7fceea0e7f23232cc657252662502b4c388762eaada9b70c21890989a615d63</cites><orcidid>0000-0003-3165-9177</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12035-019-1587-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12035-019-1587-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31062249$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ting, Lai-Lei</creatorcontrib><creatorcontrib>Lu, Hsien-Tsung</creatorcontrib><creatorcontrib>Yen, Shu-Fen</creatorcontrib><creatorcontrib>Ngo, Thi Huong</creatorcontrib><creatorcontrib>Tu, Fang-Yu</creatorcontrib><creatorcontrib>Tsai, I-Shih</creatorcontrib><creatorcontrib>Tsai, Yi-Hua</creatorcontrib><creatorcontrib>Chang, Fu-Yen</creatorcontrib><creatorcontrib>Li, Xiao-Jiang</creatorcontrib><creatorcontrib>Li, Shihua</creatorcontrib><creatorcontrib>Lee, Ching-Kuo</creatorcontrib><creatorcontrib>Kao, Shu-Huei</creatorcontrib><creatorcontrib>Kuo, Yu-Min</creatorcontrib><creatorcontrib>Lin, Yung-Feng</creatorcontrib><title>Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells</title><title>Molecular neurobiology</title><addtitle>Mol Neurobiol</addtitle><addtitle>Mol Neurobiol</addtitle><description>A hallmark of Alzheimer’s disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as
Ahi1-
knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.</description><subject>Adaptor Proteins, Vesicular Transport - metabolism</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid - metabolism</subject><subject>Amyloid beta-Protein Precursor - metabolism</subject><subject>Amyloid precursor protein</subject><subject>Amyloidogenesis</subject><subject>Animals</subject><subject>Axonogenesis</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain</subject><subject>Cell Biology</subject><subject>Cell culture</subject><subject>Cell Differentiation</subject><subject>Cell Line</subject><subject>Cell Survival</subject><subject>Culture media</subject><subject>Extracellular signal-regulated kinase</subject><subject>Genotypes</subject><subject>Hap1 protein</subject><subject>Humans</subject><subject>Huntingtin</subject><subject>Lysates</subject><subject>Mental disorders</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Biological</subject><subject>Nerve Growth Factors - metabolism</subject><subject>Neurobiology</subject><subject>Neuroblastoma</subject><subject>Neurodevelopmental disorders</subject><subject>Neurology</subject><subject>Neuroprotection</subject><subject>Neurosciences</subject><subject>Pathology</subject><subject>Plaques</subject><subject>Protein Binding</subject><subject>Translocation</subject><subject>Tropomyosin</subject><issn>0893-7648</issn><issn>1559-1182</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kMFqGzEQhkVJSNy0D9BLEeTSyzaaWWulPRonaQIJKaWlRyFrx86G3ZWrsaHOKa-R18uTRMZJC4WiwyD0za-fT4gPoD6DUuaEAVWpCwV1AdqaAt6IEWidb2BxT4yUrcvCVGN7KN4y3ymFCMociMMSVIU4rkfi59nvZSLmNg4yzuXk4hLkN-KwJpaTftPFtokLGtogv_rVbeziYiPbQU66-1tqe0pPD48sT1smzySvY0OdnFLX8TuxP_cd0_uXeSR-nJ99n14UVzdfLqeTqyKUBlcFkpkHIq_yxDKfECptUGNVoVY4G4fSWlMhed_4emZUQLC1qm3tK9BNVR6JT7vcZYq_cumV61sOuYEfKK7ZYc4EqJW2GT3-B72L6zTkdplCpQGM3VKwo0KKzInmbpna3qeNA-W21t3OusvW3da6g7zz8SV5Peup-bPxqjkDuAM4Pw0LSn-__n_qM6AQi54</recordid><startdate>20191101</startdate><enddate>20191101</enddate><creator>Ting, Lai-Lei</creator><creator>Lu, Hsien-Tsung</creator><creator>Yen, Shu-Fen</creator><creator>Ngo, Thi Huong</creator><creator>Tu, Fang-Yu</creator><creator>Tsai, I-Shih</creator><creator>Tsai, Yi-Hua</creator><creator>Chang, Fu-Yen</creator><creator>Li, Xiao-Jiang</creator><creator>Li, Shihua</creator><creator>Lee, Ching-Kuo</creator><creator>Kao, Shu-Huei</creator><creator>Kuo, Yu-Min</creator><creator>Lin, Yung-Feng</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7QR</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</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>M2M</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3165-9177</orcidid></search><sort><creationdate>20191101</creationdate><title>Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells</title><author>Ting, Lai-Lei ; Lu, Hsien-Tsung ; Yen, Shu-Fen ; Ngo, Thi Huong ; Tu, Fang-Yu ; Tsai, I-Shih ; Tsai, Yi-Hua ; Chang, Fu-Yen ; Li, Xiao-Jiang ; Li, Shihua ; Lee, Ching-Kuo ; Kao, Shu-Huei ; Kuo, Yu-Min ; Lin, Yung-Feng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-2e7fceea0e7f23232cc657252662502b4c388762eaada9b70c21890989a615d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adaptor Proteins, Vesicular Transport - metabolism</topic><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid - metabolism</topic><topic>Amyloid beta-Protein Precursor - metabolism</topic><topic>Amyloid precursor protein</topic><topic>Amyloidogenesis</topic><topic>Animals</topic><topic>Axonogenesis</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain</topic><topic>Cell Biology</topic><topic>Cell culture</topic><topic>Cell Differentiation</topic><topic>Cell Line</topic><topic>Cell Survival</topic><topic>Culture media</topic><topic>Extracellular signal-regulated kinase</topic><topic>Genotypes</topic><topic>Hap1 protein</topic><topic>Humans</topic><topic>Huntingtin</topic><topic>Lysates</topic><topic>Mental disorders</topic><topic>Mice, Inbred C57BL</topic><topic>Models, Biological</topic><topic>Nerve Growth Factors - metabolism</topic><topic>Neurobiology</topic><topic>Neuroblastoma</topic><topic>Neurodevelopmental disorders</topic><topic>Neurology</topic><topic>Neuroprotection</topic><topic>Neurosciences</topic><topic>Pathology</topic><topic>Plaques</topic><topic>Protein Binding</topic><topic>Translocation</topic><topic>Tropomyosin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ting, Lai-Lei</creatorcontrib><creatorcontrib>Lu, Hsien-Tsung</creatorcontrib><creatorcontrib>Yen, Shu-Fen</creatorcontrib><creatorcontrib>Ngo, Thi Huong</creatorcontrib><creatorcontrib>Tu, Fang-Yu</creatorcontrib><creatorcontrib>Tsai, I-Shih</creatorcontrib><creatorcontrib>Tsai, Yi-Hua</creatorcontrib><creatorcontrib>Chang, Fu-Yen</creatorcontrib><creatorcontrib>Li, Xiao-Jiang</creatorcontrib><creatorcontrib>Li, Shihua</creatorcontrib><creatorcontrib>Lee, Ching-Kuo</creatorcontrib><creatorcontrib>Kao, Shu-Huei</creatorcontrib><creatorcontrib>Kuo, Yu-Min</creatorcontrib><creatorcontrib>Lin, Yung-Feng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Psychology Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular neurobiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ting, Lai-Lei</au><au>Lu, Hsien-Tsung</au><au>Yen, Shu-Fen</au><au>Ngo, Thi Huong</au><au>Tu, Fang-Yu</au><au>Tsai, I-Shih</au><au>Tsai, Yi-Hua</au><au>Chang, Fu-Yen</au><au>Li, Xiao-Jiang</au><au>Li, Shihua</au><au>Lee, Ching-Kuo</au><au>Kao, Shu-Huei</au><au>Kuo, Yu-Min</au><au>Lin, Yung-Feng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells</atitle><jtitle>Molecular neurobiology</jtitle><stitle>Mol Neurobiol</stitle><addtitle>Mol Neurobiol</addtitle><date>2019-11-01</date><risdate>2019</risdate><volume>56</volume><issue>11</issue><spage>7572</spage><epage>7582</epage><pages>7572-7582</pages><issn>0893-7648</issn><eissn>1559-1182</eissn><abstract>A hallmark of Alzheimer’s disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as
Ahi1-
knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>31062249</pmid><doi>10.1007/s12035-019-1587-1</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-3165-9177</orcidid></addata></record> |
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subjects | Adaptor Proteins, Vesicular Transport - metabolism Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Amyloid - metabolism Amyloid beta-Protein Precursor - metabolism Amyloid precursor protein Amyloidogenesis Animals Axonogenesis Biomedical and Life Sciences Biomedicine Brain Cell Biology Cell culture Cell Differentiation Cell Line Cell Survival Culture media Extracellular signal-regulated kinase Genotypes Hap1 protein Humans Huntingtin Lysates Mental disorders Mice, Inbred C57BL Models, Biological Nerve Growth Factors - metabolism Neurobiology Neuroblastoma Neurodevelopmental disorders Neurology Neuroprotection Neurosciences Pathology Plaques Protein Binding Translocation Tropomyosin |
title | Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells |
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