Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4
Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-09, Vol.67 (17), p.15061-15079 |
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| creator | Velma, Ganga Reddy Laham, Megan S Lewandowski, Cutler Valencia-Olvera, Ana C Balu, Deebika Moore, Annabelle Ackerman-Berrier, Martha Rychetsky, Pavel Penton, Christopher Musku, Soumya Reddy Annadurai, Anandhan Sulaiman, Maha Ibrahim Ma, Nina J Thatcher, Gregory R |
| description | Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because
is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound
that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with
increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human
-expressing model with hallmark amyloid-β pathology. |
| doi_str_mv | 10.1021/acs.jmedchem.4c00733 |
| format | Article |
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is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound
that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with
increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human
-expressing model with hallmark amyloid-β pathology.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.4c00733</identifier><identifier>PMID: 39191400</identifier><language>eng</language><publisher>United States</publisher><subject>Alzheimer Disease - drug therapy ; Alzheimer Disease - metabolism ; Animals ; Apolipoprotein E3 - genetics ; Apolipoprotein E3 - metabolism ; Apolipoprotein E4 - genetics ; Apolipoprotein E4 - metabolism ; ATP Binding Cassette Transporter 1 - genetics ; ATP Binding Cassette Transporter 1 - metabolism ; Disease Models, Animal ; Humans ; Liver X Receptors - agonists ; Liver X Receptors - metabolism ; Mice ; Mice, Transgenic ; Presenilin-1 - genetics ; Presenilin-1 - metabolism</subject><ispartof>Journal of medicinal chemistry, 2024-09, Vol.67 (17), p.15061-15079</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c186t-b0ea9bab7a56c231a8f0e06a17aedf3a835ab0f53f7dbf9307b6a9613bc73c1e3</cites><orcidid>0000-0001-5054-2519 ; 0000-0002-7757-1739</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,2752,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39191400$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Velma, Ganga Reddy</creatorcontrib><creatorcontrib>Laham, Megan S</creatorcontrib><creatorcontrib>Lewandowski, Cutler</creatorcontrib><creatorcontrib>Valencia-Olvera, Ana C</creatorcontrib><creatorcontrib>Balu, Deebika</creatorcontrib><creatorcontrib>Moore, Annabelle</creatorcontrib><creatorcontrib>Ackerman-Berrier, Martha</creatorcontrib><creatorcontrib>Rychetsky, Pavel</creatorcontrib><creatorcontrib>Penton, Christopher</creatorcontrib><creatorcontrib>Musku, Soumya Reddy</creatorcontrib><creatorcontrib>Annadurai, Anandhan</creatorcontrib><creatorcontrib>Sulaiman, Maha Ibrahim</creatorcontrib><creatorcontrib>Ma, Nina</creatorcontrib><creatorcontrib>J Thatcher, Gregory R</creatorcontrib><title>Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because
is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound
that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with
increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human
-expressing model with hallmark amyloid-β pathology.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - metabolism</subject><subject>Animals</subject><subject>Apolipoprotein E3 - genetics</subject><subject>Apolipoprotein E3 - metabolism</subject><subject>Apolipoprotein E4 - genetics</subject><subject>Apolipoprotein E4 - metabolism</subject><subject>ATP Binding Cassette Transporter 1 - genetics</subject><subject>ATP Binding Cassette Transporter 1 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Humans</subject><subject>Liver X Receptors - agonists</subject><subject>Liver X Receptors - metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Presenilin-1 - genetics</subject><subject>Presenilin-1 - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOw0AMRUcIBKXwBwjNjrJI8cR5LkMpUKkFFsA2ciYODMqjzDQS8PUEUdjYkn2vr3WEOFEwVeCrC9Ju-tZwqV-5mQYaIEbcESMV-uAFCQS7YgTg-54f-XggDp17AwBUPu6LA0xVqgKAkbB3XVubdffCrdEyu5xlSi7astdsnZzcLbPFuaw6K7P665VNw_bMySvjmBzLZ6pNSRsupWklyVXXD8NVV3It5x9ry86Z9kXe9g21Mnu4n-PFTw2OxF5FtePjbR-Lp-v54-zWW97fLGbZ0tMqiTZeAUxpQUVMYaR9VJRUwBCRionLCinBkAqoQqzisqhShLiIKI0UFjpGrRjHYvJ7d227957dJm-M01zX1PLwao6QxkkISYKDNPiVats5Z7nK19Y0ZD9zBfkP7Xygnf_Rzre0B9vpNqEvht2_6Q8vfgPLj30z</recordid><startdate>20240912</startdate><enddate>20240912</enddate><creator>Velma, Ganga Reddy</creator><creator>Laham, Megan S</creator><creator>Lewandowski, Cutler</creator><creator>Valencia-Olvera, Ana C</creator><creator>Balu, Deebika</creator><creator>Moore, Annabelle</creator><creator>Ackerman-Berrier, Martha</creator><creator>Rychetsky, Pavel</creator><creator>Penton, Christopher</creator><creator>Musku, Soumya Reddy</creator><creator>Annadurai, Anandhan</creator><creator>Sulaiman, Maha Ibrahim</creator><creator>Ma, Nina</creator><creator>J Thatcher, Gregory R</creator><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><orcidid>https://orcid.org/0000-0001-5054-2519</orcidid><orcidid>https://orcid.org/0000-0002-7757-1739</orcidid></search><sort><creationdate>20240912</creationdate><title>Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4</title><author>Velma, Ganga Reddy ; Laham, Megan S ; Lewandowski, Cutler ; Valencia-Olvera, Ana C ; Balu, Deebika ; Moore, Annabelle ; Ackerman-Berrier, Martha ; Rychetsky, Pavel ; Penton, Christopher ; Musku, Soumya Reddy ; Annadurai, Anandhan ; Sulaiman, Maha Ibrahim ; Ma, Nina ; J Thatcher, Gregory R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c186t-b0ea9bab7a56c231a8f0e06a17aedf3a835ab0f53f7dbf9307b6a9613bc73c1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - metabolism</topic><topic>Animals</topic><topic>Apolipoprotein E3 - genetics</topic><topic>Apolipoprotein E3 - metabolism</topic><topic>Apolipoprotein E4 - genetics</topic><topic>Apolipoprotein E4 - metabolism</topic><topic>ATP Binding Cassette Transporter 1 - genetics</topic><topic>ATP Binding Cassette Transporter 1 - metabolism</topic><topic>Disease Models, Animal</topic><topic>Humans</topic><topic>Liver X Receptors - agonists</topic><topic>Liver X Receptors - metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Presenilin-1 - genetics</topic><topic>Presenilin-1 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Velma, Ganga Reddy</creatorcontrib><creatorcontrib>Laham, Megan S</creatorcontrib><creatorcontrib>Lewandowski, Cutler</creatorcontrib><creatorcontrib>Valencia-Olvera, Ana C</creatorcontrib><creatorcontrib>Balu, Deebika</creatorcontrib><creatorcontrib>Moore, Annabelle</creatorcontrib><creatorcontrib>Ackerman-Berrier, Martha</creatorcontrib><creatorcontrib>Rychetsky, Pavel</creatorcontrib><creatorcontrib>Penton, Christopher</creatorcontrib><creatorcontrib>Musku, Soumya Reddy</creatorcontrib><creatorcontrib>Annadurai, Anandhan</creatorcontrib><creatorcontrib>Sulaiman, Maha Ibrahim</creatorcontrib><creatorcontrib>Ma, Nina</creatorcontrib><creatorcontrib>J Thatcher, Gregory R</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Velma, Ganga Reddy</au><au>Laham, Megan S</au><au>Lewandowski, Cutler</au><au>Valencia-Olvera, Ana C</au><au>Balu, Deebika</au><au>Moore, Annabelle</au><au>Ackerman-Berrier, Martha</au><au>Rychetsky, Pavel</au><au>Penton, Christopher</au><au>Musku, Soumya Reddy</au><au>Annadurai, Anandhan</au><au>Sulaiman, Maha Ibrahim</au><au>Ma, Nina</au><au>J Thatcher, Gregory R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2024-09-12</date><risdate>2024</risdate><volume>67</volume><issue>17</issue><spage>15061</spage><epage>15079</epage><pages>15061-15079</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because
is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound
that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with
increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human
-expressing model with hallmark amyloid-β pathology.</abstract><cop>United States</cop><pmid>39191400</pmid><doi>10.1021/acs.jmedchem.4c00733</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0001-5054-2519</orcidid><orcidid>https://orcid.org/0000-0002-7757-1739</orcidid></addata></record> |
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| source | ACS Publications; MEDLINE |
| subjects | Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Animals Apolipoprotein E3 - genetics Apolipoprotein E3 - metabolism Apolipoprotein E4 - genetics Apolipoprotein E4 - metabolism ATP Binding Cassette Transporter 1 - genetics ATP Binding Cassette Transporter 1 - metabolism Disease Models, Animal Humans Liver X Receptors - agonists Liver X Receptors - metabolism Mice Mice, Transgenic Presenilin-1 - genetics Presenilin-1 - metabolism |
| title | Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4 |
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