Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model
Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a trans...
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| Veröffentlicht in: | Neuropharmacology 2018-03, Vol.130, p.54-61 |
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| creator | Smith, Levi M. Zhu, Rong Strittmatter, Stephen M. |
| description | Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a transgenic model. Aged APPswe/PS1ΔE9 mice were treated with saracatinib or memantine for 4 weeks and spatial memory improved to control levels. After drug washout, there was sustained rescue of both memory function and synapse density by saracatinib, but a loss of benefit from memantine. These data demonstrate a disease-modifying persistent benefit for saracatinib in a preclinincal Alzheimer's model, and distinguish its action from that of memantine.
•Disease-modifying effects of saracatinib or memantine were assessed in vivo.•Saracatinib but not memantine exhibited persistent rescue of synapses and memory.•Saracatinib benefit was observed at least one month after therapy discontinuation.•Withdrawal study design can differentiate disease-modifying and symptomatic agents. |
| doi_str_mv | 10.1016/j.neuropharm.2017.11.042 |
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•Disease-modifying effects of saracatinib or memantine were assessed in vivo.•Saracatinib but not memantine exhibited persistent rescue of synapses and memory.•Saracatinib benefit was observed at least one month after therapy discontinuation.•Withdrawal study design can differentiate disease-modifying and symptomatic agents.</description><identifier>ISSN: 0028-3908</identifier><identifier>EISSN: 1873-7064</identifier><identifier>DOI: 10.1016/j.neuropharm.2017.11.042</identifier><identifier>PMID: 29191754</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Alzheimer Disease - drug therapy ; Alzheimer Disease - metabolism ; Alzheimer's disease ; Amyloid beta-Peptides - metabolism ; Animals ; APPswe/PS1ΔE9 mice ; AZD0530 ; Benzodioxoles - pharmacology ; Fyn kinase ; Maze Learning - drug effects ; Memantine ; Memantine - pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia - drug effects ; Microglia - pathology ; Namenda ; Nootropic Agents - pharmacology ; Proto-Oncogene Proteins c-fyn - antagonists & inhibitors ; Proto-Oncogene Proteins c-fyn - metabolism ; Quinazolines - pharmacology ; Recognition (Psychology) ; Saracatinib ; Spatial Learning - drug effects ; Spatial Memory - drug effects ; Spatial Navigation - drug effects ; Synapses - drug effects</subject><ispartof>Neuropharmacology, 2018-03, Vol.130, p.54-61</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-63c8dcc870dc99a5b20f51ed6ef8a8728af3db2c0384dd9251013ee6f960113b3</citedby><cites>FETCH-LOGICAL-c479t-63c8dcc870dc99a5b20f51ed6ef8a8728af3db2c0384dd9251013ee6f960113b3</cites><orcidid>0000-0001-8188-3092</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neuropharm.2017.11.042$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29191754$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smith, Levi M.</creatorcontrib><creatorcontrib>Zhu, Rong</creatorcontrib><creatorcontrib>Strittmatter, Stephen M.</creatorcontrib><title>Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model</title><title>Neuropharmacology</title><addtitle>Neuropharmacology</addtitle><description>Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a transgenic model. Aged APPswe/PS1ΔE9 mice were treated with saracatinib or memantine for 4 weeks and spatial memory improved to control levels. After drug washout, there was sustained rescue of both memory function and synapse density by saracatinib, but a loss of benefit from memantine. These data demonstrate a disease-modifying persistent benefit for saracatinib in a preclinincal Alzheimer's model, and distinguish its action from that of memantine.
•Disease-modifying effects of saracatinib or memantine were assessed in vivo.•Saracatinib but not memantine exhibited persistent rescue of synapses and memory.•Saracatinib benefit was observed at least one month after therapy discontinuation.•Withdrawal study design can differentiate disease-modifying and symptomatic agents.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animals</subject><subject>APPswe/PS1ΔE9 mice</subject><subject>AZD0530</subject><subject>Benzodioxoles - pharmacology</subject><subject>Fyn kinase</subject><subject>Maze Learning - drug effects</subject><subject>Memantine</subject><subject>Memantine - pharmacology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Microglia - drug effects</subject><subject>Microglia - pathology</subject><subject>Namenda</subject><subject>Nootropic Agents - pharmacology</subject><subject>Proto-Oncogene Proteins c-fyn - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-fyn - metabolism</subject><subject>Quinazolines - pharmacology</subject><subject>Recognition (Psychology)</subject><subject>Saracatinib</subject><subject>Spatial Learning - drug effects</subject><subject>Spatial Memory - drug effects</subject><subject>Spatial Navigation - drug effects</subject><subject>Synapses - drug effects</subject><issn>0028-3908</issn><issn>1873-7064</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi0EokvhLyDf4JLgsRPHuSCVQgGpEhc4cbAce9z1ktiLnRQtv56sthQ4cRpp5p13Ph5CKLAaGMhXuzriktN-a_JUcwZdDVCzhj8gG1CdqDomm4dkwxhXleiZOiNPStkxxhoF6jE54z300LXNhnx9GwqagtWUXPCHEG_ogBF9mGny9OoQ6TAm-804pHvMJZS5UONnzPSHKdu0zDREOqWlIL0Yf24xTJhflDXjcHxKHnkzFnx2F8_Jl6t3ny8_VNef3n-8vLiubNP1cyWFVc5a1TFn-960A2e-BXQSvTKq48p44QZumVCNcz1v1xcIROl7yQDEIM7J65PvfhkmdBbjnM2o9zlMJh90MkH_W4lhq2_SrW67RkimVoOXdwY5fV-wzHoKxeI4mojraRr6DqSQwI9SdZLanErJ6O_HANNHNnqn_7DRRzYaQK9s1tbnf6953_gbxip4cxLg-qzbgFkXGzBadCGjnbVL4f9TfgEqKag1</recordid><startdate>20180301</startdate><enddate>20180301</enddate><creator>Smith, Levi M.</creator><creator>Zhu, Rong</creator><creator>Strittmatter, Stephen M.</creator><general>Elsevier Ltd</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>5PM</scope><orcidid>https://orcid.org/0000-0001-8188-3092</orcidid></search><sort><creationdate>20180301</creationdate><title>Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model</title><author>Smith, Levi M. ; Zhu, Rong ; Strittmatter, Stephen M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c479t-63c8dcc870dc99a5b20f51ed6ef8a8728af3db2c0384dd9251013ee6f960113b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer's disease</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Animals</topic><topic>APPswe/PS1ΔE9 mice</topic><topic>AZD0530</topic><topic>Benzodioxoles - pharmacology</topic><topic>Fyn kinase</topic><topic>Maze Learning - drug effects</topic><topic>Memantine</topic><topic>Memantine - pharmacology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Microglia - drug effects</topic><topic>Microglia - pathology</topic><topic>Namenda</topic><topic>Nootropic Agents - pharmacology</topic><topic>Proto-Oncogene Proteins c-fyn - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-fyn - metabolism</topic><topic>Quinazolines - pharmacology</topic><topic>Recognition (Psychology)</topic><topic>Saracatinib</topic><topic>Spatial Learning - drug effects</topic><topic>Spatial Memory - drug effects</topic><topic>Spatial Navigation - drug effects</topic><topic>Synapses - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smith, Levi M.</creatorcontrib><creatorcontrib>Zhu, Rong</creatorcontrib><creatorcontrib>Strittmatter, Stephen 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>PubMed Central (Full Participant titles)</collection><jtitle>Neuropharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smith, Levi M.</au><au>Zhu, Rong</au><au>Strittmatter, Stephen M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model</atitle><jtitle>Neuropharmacology</jtitle><addtitle>Neuropharmacology</addtitle><date>2018-03-01</date><risdate>2018</risdate><volume>130</volume><spage>54</spage><epage>61</epage><pages>54-61</pages><issn>0028-3908</issn><eissn>1873-7064</eissn><abstract>Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a transgenic model. Aged APPswe/PS1ΔE9 mice were treated with saracatinib or memantine for 4 weeks and spatial memory improved to control levels. After drug washout, there was sustained rescue of both memory function and synapse density by saracatinib, but a loss of benefit from memantine. These data demonstrate a disease-modifying persistent benefit for saracatinib in a preclinincal Alzheimer's model, and distinguish its action from that of memantine.
•Disease-modifying effects of saracatinib or memantine were assessed in vivo.•Saracatinib but not memantine exhibited persistent rescue of synapses and memory.•Saracatinib benefit was observed at least one month after therapy discontinuation.•Withdrawal study design can differentiate disease-modifying and symptomatic agents.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29191754</pmid><doi>10.1016/j.neuropharm.2017.11.042</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-8188-3092</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Alzheimer's disease Amyloid beta-Peptides - metabolism Animals APPswe/PS1ΔE9 mice AZD0530 Benzodioxoles - pharmacology Fyn kinase Maze Learning - drug effects Memantine Memantine - pharmacology Mice Mice, Inbred C57BL Mice, Transgenic Microglia - drug effects Microglia - pathology Namenda Nootropic Agents - pharmacology Proto-Oncogene Proteins c-fyn - antagonists & inhibitors Proto-Oncogene Proteins c-fyn - metabolism Quinazolines - pharmacology Recognition (Psychology) Saracatinib Spatial Learning - drug effects Spatial Memory - drug effects Spatial Navigation - drug effects Synapses - drug effects |
| title | Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model |
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