Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice
Though the precise cause(s) of Alzheimer's disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE...
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| Veröffentlicht in: | Molecular neurodegeneration 2013-06, Vol.8 (1), p.18-18, Article 18 |
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| creator | LaClair, Katherine D Manaye, Kebreten F Lee, Dexter L Allard, Joanne S Savonenko, Alena V Troncoso, Juan C Wong, Philip C |
| description | Though the precise cause(s) of Alzheimer's disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs). Drugs that activate RXRs, including bexarotene, can increase APOE and ABCA1 production, and have been shown to decrease the Aβ burden and improve cognition in mouse models of Aβ amyloidosis. Although recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial.
In efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice.
We recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy. |
| doi_str_mv | 10.1186/1750-1326-8-18 |
| format | Article |
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In efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice.
We recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy.</description><identifier>ISSN: 1750-1326</identifier><identifier>EISSN: 1750-1326</identifier><identifier>DOI: 10.1186/1750-1326-8-18</identifier><identifier>PMID: 23764200</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Advertising executives ; Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer's disease ; Animals ; Anticarcinogenic Agents - pharmacology ; Apolipoproteins ; Apolipoproteins E - biosynthesis ; ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters - biosynthesis ; Behavior, Animal - drug effects ; Blotting, Western ; Brain ; Disease Models, Animal ; Drug therapy ; Female ; Females ; Gender differences ; Health aspects ; Male ; Medicine ; Memory ; Memory - drug effects ; Mice ; Mice, Mutant Strains ; Molecular weight ; Physiological aspects ; Plaque, Amyloid - metabolism ; Plaque, Amyloid - pathology ; Proteins ; Rodents ; Short Report ; Software ; Statistics ; Tetrahydronaphthalenes - pharmacology</subject><ispartof>Molecular neurodegeneration, 2013-06, Vol.8 (1), p.18-18, Article 18</ispartof><rights>COPYRIGHT 2013 BioMed Central Ltd.</rights><rights>2013 LaClair et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright © 2013 LaClair et al.; licensee BioMed Central Ltd. 2013 LaClair et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b576t-91a18f4932ea130394d405ede4d91188bededd6927274e786c0d9f09dc43dd713</citedby><cites>FETCH-LOGICAL-b576t-91a18f4932ea130394d405ede4d91188bededd6927274e786c0d9f09dc43dd713</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/PMC3693923/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693923/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23764200$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LaClair, Katherine D</creatorcontrib><creatorcontrib>Manaye, Kebreten F</creatorcontrib><creatorcontrib>Lee, Dexter L</creatorcontrib><creatorcontrib>Allard, Joanne S</creatorcontrib><creatorcontrib>Savonenko, Alena V</creatorcontrib><creatorcontrib>Troncoso, Juan C</creatorcontrib><creatorcontrib>Wong, Philip C</creatorcontrib><title>Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice</title><title>Molecular neurodegeneration</title><addtitle>Mol Neurodegener</addtitle><description>Though the precise cause(s) of Alzheimer's disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs). Drugs that activate RXRs, including bexarotene, can increase APOE and ABCA1 production, and have been shown to decrease the Aβ burden and improve cognition in mouse models of Aβ amyloidosis. Although recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial.
In efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice.
We recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy.</description><subject>Advertising executives</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Animals</subject><subject>Anticarcinogenic Agents - pharmacology</subject><subject>Apolipoproteins</subject><subject>Apolipoproteins E - biosynthesis</subject><subject>ATP Binding Cassette Transporter 1</subject><subject>ATP-Binding Cassette Transporters - biosynthesis</subject><subject>Behavior, Animal - drug effects</subject><subject>Blotting, Western</subject><subject>Brain</subject><subject>Disease Models, Animal</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Females</subject><subject>Gender differences</subject><subject>Health aspects</subject><subject>Male</subject><subject>Medicine</subject><subject>Memory</subject><subject>Memory - drug effects</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Molecular weight</subject><subject>Physiological aspects</subject><subject>Plaque, Amyloid - metabolism</subject><subject>Plaque, Amyloid - pathology</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Short Report</subject><subject>Software</subject><subject>Statistics</subject><subject>Tetrahydronaphthalenes - pharmacology</subject><issn>1750-1326</issn><issn>1750-1326</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkk1v1DAQhiMEoqVw5YgsceHQtP6KE1-QVlX5kCqxEuVsOfFk11VihzhZQPx5JrQsLRQJ-eCR55nX9juTZc8ZPWGsUqesLGjOBFd5lbPqQXa4P3h4Kz7InqR0RaksKS0eZwdclEpySg-z75cj2KmHMJEvftqSGr7aMU4Q4JhY0sR-iHNwZNraifjQIJwgETvEzg9xWEgf8vNjguHOO0yFiFWb4Ce_A1QL0PqlkvTzZPGS1Xp9uv7ISO8beJo9am2X4NnNfpR9enN-efYuv_jw9v3Z6iKvi1JNuWaWVa3UgoNlggotnaQFOJBOowdVjaFzSvOSlxLKSjXU6ZZq10jhXMnEUfb6WneY6x5cg58dbWeG0fd2_Gai9eZuJvit2cSdEUoLzQUKrK4Fah__IXA3g76ZxXyzmG8qwyrUeHXziDF-niFNpvepga6zAeKckNRac8or-R9oyZVWSi6qL_9Ar-I8BnTzJ1XqQlTsN7WxHRgf2oivbBZRsyqEXGZBUqRO7qFwOcBuxaWTeH5fQTPGlEZo944w_DlO598evLjdiD3-axzFD1Yz31M</recordid><startdate>20130613</startdate><enddate>20130613</enddate><creator>LaClair, Katherine D</creator><creator>Manaye, Kebreten F</creator><creator>Lee, Dexter L</creator><creator>Allard, Joanne S</creator><creator>Savonenko, Alena V</creator><creator>Troncoso, Juan C</creator><creator>Wong, Philip C</creator><general>BioMed Central Ltd</general><general>BioMed Central</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>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130613</creationdate><title>Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice</title><author>LaClair, Katherine D ; 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Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs). Drugs that activate RXRs, including bexarotene, can increase APOE and ABCA1 production, and have been shown to decrease the Aβ burden and improve cognition in mouse models of Aβ amyloidosis. Although recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial.
In efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice.
We recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>23764200</pmid><doi>10.1186/1750-1326-8-18</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Advertising executives Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Animals Anticarcinogenic Agents - pharmacology Apolipoproteins Apolipoproteins E - biosynthesis ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters - biosynthesis Behavior, Animal - drug effects Blotting, Western Brain Disease Models, Animal Drug therapy Female Females Gender differences Health aspects Male Medicine Memory Memory - drug effects Mice Mice, Mutant Strains Molecular weight Physiological aspects Plaque, Amyloid - metabolism Plaque, Amyloid - pathology Proteins Rodents Short Report Software Statistics Tetrahydronaphthalenes - pharmacology |
| title | Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice |
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