Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid β-peptide 1–42 (Aβ42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and...
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Veröffentlicht in: | The Journal of clinical investigation 2004-12, Vol.114 (11), p.1624-1634 |
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creator | Gong, Bing Vitolo, Ottavio V. Trinchese, Fabrizio Liu, Shumin Shelanski, Michael Arancio, Ottavio |
description | Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid β-peptide 1–42 (Aβ42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for
amyloid precursor protein
(AA substitution K670N,M671L) and
presenilin-1
(AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element–binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Aβ. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Aβ42 levels. |
doi_str_mv | 10.1172/JCI200422831 |
format | Article |
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amyloid precursor protein
(AA substitution K670N,M671L) and
presenilin-1
(AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element–binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Aβ. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Aβ42 levels.</description><identifier>ISSN: 0021-9738</identifier><identifier>DOI: 10.1172/JCI200422831</identifier><identifier>PMID: 15578094</identifier><language>eng</language><publisher>American Society for Clinical Investigation</publisher><ispartof>The Journal of clinical investigation, 2004-12, Vol.114 (11), p.1624-1634</ispartof><rights>Copyright © 2004, American Society for Clinical Investigation 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c286t-598ba81c678abd91d5b6d9c8e1b706f7c28fc077868bd29630da7551dbe25fe43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC529285/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC529285/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Gong, Bing</creatorcontrib><creatorcontrib>Vitolo, Ottavio V.</creatorcontrib><creatorcontrib>Trinchese, Fabrizio</creatorcontrib><creatorcontrib>Liu, Shumin</creatorcontrib><creatorcontrib>Shelanski, Michael</creatorcontrib><creatorcontrib>Arancio, Ottavio</creatorcontrib><title>Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment</title><title>The Journal of clinical investigation</title><description>Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid β-peptide 1–42 (Aβ42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for
amyloid precursor protein
(AA substitution K670N,M671L) and
presenilin-1
(AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element–binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Aβ. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Aβ42 levels.</description><issn>0021-9738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNpVTbtOwzAA9ACipbDxAf6BgO3EsT0wVBWPokowwBz5ldYotiPbrVS-nhRYWO5Od6c7AG4wusWYkbuX1Zog1BDCa3wG5ggRXAlW8xm4zPkTIdw0tLkAM0wp40g0cxDfbMouFxsKdH5M8WD9jw4wH4Mci9NQBgN13AZX3MHCfh90cTHkU0cGuBy-dtZ5m6CP-2wnNHaAsi-Tk-LgxiQ9LMnKchq-Aue9HLK9_uMF-Hh8eF89V5vXp_Vquak04W2pqOBKcqxbxqUyAhuqWiM0t1gx1PZsavUaMcZbrgwRbY2MZJRioyyhvW3qBbj_3R33ylujp-skh25Mzst07KJ03f8kuF23jYeOEkE4rb8BHqhorg</recordid><startdate>20041201</startdate><enddate>20041201</enddate><creator>Gong, Bing</creator><creator>Vitolo, Ottavio V.</creator><creator>Trinchese, Fabrizio</creator><creator>Liu, Shumin</creator><creator>Shelanski, Michael</creator><creator>Arancio, Ottavio</creator><general>American Society for Clinical Investigation</general><scope>5PM</scope></search><sort><creationdate>20041201</creationdate><title>Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment</title><author>Gong, Bing ; Vitolo, Ottavio V. ; Trinchese, Fabrizio ; Liu, Shumin ; Shelanski, Michael ; Arancio, Ottavio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c286t-598ba81c678abd91d5b6d9c8e1b706f7c28fc077868bd29630da7551dbe25fe43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gong, Bing</creatorcontrib><creatorcontrib>Vitolo, Ottavio V.</creatorcontrib><creatorcontrib>Trinchese, Fabrizio</creatorcontrib><creatorcontrib>Liu, Shumin</creatorcontrib><creatorcontrib>Shelanski, Michael</creatorcontrib><creatorcontrib>Arancio, Ottavio</creatorcontrib><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gong, Bing</au><au>Vitolo, Ottavio V.</au><au>Trinchese, Fabrizio</au><au>Liu, Shumin</au><au>Shelanski, Michael</au><au>Arancio, Ottavio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment</atitle><jtitle>The Journal of clinical investigation</jtitle><date>2004-12-01</date><risdate>2004</risdate><volume>114</volume><issue>11</issue><spage>1624</spage><epage>1634</epage><pages>1624-1634</pages><issn>0021-9738</issn><abstract>Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid β-peptide 1–42 (Aβ42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for
amyloid precursor protein
(AA substitution K670N,M671L) and
presenilin-1
(AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element–binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Aβ. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Aβ42 levels.</abstract><pub>American Society for Clinical Investigation</pub><pmid>15578094</pmid><doi>10.1172/JCI200422831</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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title | Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment |
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