Loading…

ADAM10 Missense Mutations Potentiate [beta]-Amyloid Accumulation by Impairing Prodomain Chaperone Function

The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by [alpha]-secretase cleavage within the Aβ domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, tha...

Full description

Saved in:
Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2013-10, Vol.80 (2), p.385
Main Authors: Suh, Jaehong, Choi, Se Hoon, Romano, Donna M, Gannon, Moira A, Lesinski, Andrea N, Kim, Doo Yeon, Tanzi, Rudolph E
Format: Article
Language:English
Subjects:
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites
container_end_page
container_issue 2
container_start_page 385
container_title Neuron (Cambridge, Mass.)
container_volume 80
creator Suh, Jaehong
Choi, Se Hoon
Romano, Donna M
Gannon, Moira A
Lesinski, Andrea N
Kim, Doo Yeon
Tanzi, Rudolph E
description The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by [alpha]-secretase cleavage within the Aβ domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated [alpha]-secretase activity of ADAM10 and shifted APP processing toward β-secretase-mediated cleavage, while enhancing Aβ plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished [alpha]-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease.
doi_str_mv 10.1016/j.neuron.2013.08.035
format article
fullrecord <record><control><sourceid>proquest</sourceid><recordid>TN_cdi_proquest_journals_1552020236</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3396557451</sourcerecordid><originalsourceid>FETCH-proquest_journals_15520202363</originalsourceid><addsrcrecordid>eNqNzr1Ow0AQBOATAgnz8wYUK1H72PXFTlxagSgUllLQIRRdnAXOsu_M_RR5ewziAdAUU8xXjBB3hJKQqodeWk7eWVkgKYkriao8ExlhvcwXVNfnIsNVXeVVsVSX4iqEHpEWZU2Z6JvHpiWE1oTANjC0KeponA2wc5FtNDoyvB446re8GU-DM0doui6Nafh1cDjB8zhp4439gJ13RzdqY2H9qSeePzFsku1-5I24eNdD4Nu_vhb3m6eX9TafvPtKHOK-d8nbedpTWRY4R1Xqf-ob3RFQqQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1552020236</pqid></control><display><type>article</type><title>ADAM10 Missense Mutations Potentiate [beta]-Amyloid Accumulation by Impairing Prodomain Chaperone Function</title><source>BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS</source><creator>Suh, Jaehong ; Choi, Se Hoon ; Romano, Donna M ; Gannon, Moira A ; Lesinski, Andrea N ; Kim, Doo Yeon ; Tanzi, Rudolph E</creator><creatorcontrib>Suh, Jaehong ; Choi, Se Hoon ; Romano, Donna M ; Gannon, Moira A ; Lesinski, Andrea N ; Kim, Doo Yeon ; Tanzi, Rudolph E</creatorcontrib><description>The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by [alpha]-secretase cleavage within the Aβ domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated [alpha]-secretase activity of ADAM10 and shifted APP processing toward β-secretase-mediated cleavage, while enhancing Aβ plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished [alpha]-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease.</description><identifier>ISSN: 0896-6273</identifier><identifier>EISSN: 1097-4199</identifier><identifier>DOI: 10.1016/j.neuron.2013.08.035</identifier><language>eng</language><publisher>Cambridge: Elsevier Limited</publisher><subject>Alzheimer's disease ; Genes ; Mutation ; Rodents ; Transgenic animals</subject><ispartof>Neuron (Cambridge, Mass.), 2013-10, Vol.80 (2), p.385</ispartof><rights>Copyright Elsevier Limited Oct 16, 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Suh, Jaehong</creatorcontrib><creatorcontrib>Choi, Se Hoon</creatorcontrib><creatorcontrib>Romano, Donna M</creatorcontrib><creatorcontrib>Gannon, Moira A</creatorcontrib><creatorcontrib>Lesinski, Andrea N</creatorcontrib><creatorcontrib>Kim, Doo Yeon</creatorcontrib><creatorcontrib>Tanzi, Rudolph E</creatorcontrib><title>ADAM10 Missense Mutations Potentiate [beta]-Amyloid Accumulation by Impairing Prodomain Chaperone Function</title><title>Neuron (Cambridge, Mass.)</title><description>The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by [alpha]-secretase cleavage within the Aβ domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated [alpha]-secretase activity of ADAM10 and shifted APP processing toward β-secretase-mediated cleavage, while enhancing Aβ plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished [alpha]-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease.</description><subject>Alzheimer's disease</subject><subject>Genes</subject><subject>Mutation</subject><subject>Rodents</subject><subject>Transgenic animals</subject><issn>0896-6273</issn><issn>1097-4199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNqNzr1Ow0AQBOATAgnz8wYUK1H72PXFTlxagSgUllLQIRRdnAXOsu_M_RR5ewziAdAUU8xXjBB3hJKQqodeWk7eWVkgKYkriao8ExlhvcwXVNfnIsNVXeVVsVSX4iqEHpEWZU2Z6JvHpiWE1oTANjC0KeponA2wc5FtNDoyvB446re8GU-DM0doui6Nafh1cDjB8zhp4439gJ13RzdqY2H9qSeePzFsku1-5I24eNdD4Nu_vhb3m6eX9TafvPtKHOK-d8nbedpTWRY4R1Xqf-ob3RFQqQ</recordid><startdate>20131016</startdate><enddate>20131016</enddate><creator>Suh, Jaehong</creator><creator>Choi, Se Hoon</creator><creator>Romano, Donna M</creator><creator>Gannon, Moira A</creator><creator>Lesinski, Andrea N</creator><creator>Kim, Doo Yeon</creator><creator>Tanzi, Rudolph E</creator><general>Elsevier Limited</general><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20131016</creationdate><title>ADAM10 Missense Mutations Potentiate [beta]-Amyloid Accumulation by Impairing Prodomain Chaperone Function</title><author>Suh, Jaehong ; Choi, Se Hoon ; Romano, Donna M ; Gannon, Moira A ; Lesinski, Andrea N ; Kim, Doo Yeon ; Tanzi, Rudolph E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_15520202363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Alzheimer's disease</topic><topic>Genes</topic><topic>Mutation</topic><topic>Rodents</topic><topic>Transgenic animals</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Suh, Jaehong</creatorcontrib><creatorcontrib>Choi, Se Hoon</creatorcontrib><creatorcontrib>Romano, Donna M</creatorcontrib><creatorcontrib>Gannon, Moira A</creatorcontrib><creatorcontrib>Lesinski, Andrea N</creatorcontrib><creatorcontrib>Kim, Doo Yeon</creatorcontrib><creatorcontrib>Tanzi, Rudolph E</creatorcontrib><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Neuron (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Suh, Jaehong</au><au>Choi, Se Hoon</au><au>Romano, Donna M</au><au>Gannon, Moira A</au><au>Lesinski, Andrea N</au><au>Kim, Doo Yeon</au><au>Tanzi, Rudolph E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ADAM10 Missense Mutations Potentiate [beta]-Amyloid Accumulation by Impairing Prodomain Chaperone Function</atitle><jtitle>Neuron (Cambridge, Mass.)</jtitle><date>2013-10-16</date><risdate>2013</risdate><volume>80</volume><issue>2</issue><spage>385</spage><pages>385-</pages><issn>0896-6273</issn><eissn>1097-4199</eissn><abstract>The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by [alpha]-secretase cleavage within the Aβ domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated [alpha]-secretase activity of ADAM10 and shifted APP processing toward β-secretase-mediated cleavage, while enhancing Aβ plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished [alpha]-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease.</abstract><cop>Cambridge</cop><pub>Elsevier Limited</pub><doi>10.1016/j.neuron.2013.08.035</doi></addata></record>
fulltext fulltext
identifier ISSN: 0896-6273
ispartof Neuron (Cambridge, Mass.), 2013-10, Vol.80 (2), p.385
issn 0896-6273
1097-4199
language eng
recordid cdi_proquest_journals_1552020236
source BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS
subjects Alzheimer's disease
Genes
Mutation
Rodents
Transgenic animals
title ADAM10 Missense Mutations Potentiate [beta]-Amyloid Accumulation by Impairing Prodomain Chaperone Function
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T18%3A04%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=ADAM10%20Missense%20Mutations%20Potentiate%20%5Bbeta%5D-Amyloid%20Accumulation%20by%20Impairing%20Prodomain%20Chaperone%20Function&rft.jtitle=Neuron%20(Cambridge,%20Mass.)&rft.au=Suh,%20Jaehong&rft.date=2013-10-16&rft.volume=80&rft.issue=2&rft.spage=385&rft.pages=385-&rft.issn=0896-6273&rft.eissn=1097-4199&rft_id=info:doi/10.1016/j.neuron.2013.08.035&rft_dat=%3Cproquest%3E3396557451%3C/proquest%3E%3Cgrp_id%3Ecdi_FETCH-proquest_journals_15520202363%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1552020236&rft_id=info:pmid/&rfr_iscdi=true