Endocannabinoid regulation of amyloid-induced neuroinflammation
Abstract The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer's disease (AD). We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide...
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| Veröffentlicht in: | Neurobiology of aging 2015-11, Vol.36 (11), p.3008-3019 |
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| creator | Vázquez, Carmen Tolón, Rosa M Grande, M. Teresa Caraza, Marina Moreno, Marta Koester, Erin C Villaescusa, Borja Ruiz-Valdepeñas, Lourdes Fernández-Sánchez, Francisco Javier Cravatt, Benjamin F Hillard, Cecilia J Romero, Julián |
| description | Abstract The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer's disease (AD). We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide-degrading enzyme in a mouse model of AD (5xFAD). Pharmacologic inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines and also on the cognitive impairment, plaque deposition, and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1 mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques, and gliosis. These data reinforce the notion of a role for the EC system in neuroinflammation and open new perspectives on the relevance of modulating EC levels in the inflammed brain. |
| doi_str_mv | 10.1016/j.neurobiolaging.2015.08.003 |
| format | Article |
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Teresa ; Caraza, Marina ; Moreno, Marta ; Koester, Erin C ; Villaescusa, Borja ; Ruiz-Valdepeñas, Lourdes ; Fernández-Sánchez, Francisco Javier ; Cravatt, Benjamin F ; Hillard, Cecilia J ; Romero, Julián</creator><creatorcontrib>Vázquez, Carmen ; Tolón, Rosa M ; Grande, M. Teresa ; Caraza, Marina ; Moreno, Marta ; Koester, Erin C ; Villaescusa, Borja ; Ruiz-Valdepeñas, Lourdes ; Fernández-Sánchez, Francisco Javier ; Cravatt, Benjamin F ; Hillard, Cecilia J ; Romero, Julián</creatorcontrib><description>Abstract The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer's disease (AD). We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide-degrading enzyme in a mouse model of AD (5xFAD). Pharmacologic inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines and also on the cognitive impairment, plaque deposition, and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1 mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques, and gliosis. These data reinforce the notion of a role for the EC system in neuroinflammation and open new perspectives on the relevance of modulating EC levels in the inflammed brain.</description><identifier>ISSN: 0197-4580</identifier><identifier>EISSN: 1558-1497</identifier><identifier>DOI: 10.1016/j.neurobiolaging.2015.08.003</identifier><identifier>PMID: 26362942</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alzheimer Disease - drug therapy ; Alzheimer Disease - genetics ; Amidohydrolases - genetics ; Amidohydrolases - metabolism ; Amidohydrolases - physiology ; Amyloid ; Amyloid - metabolism ; Animals ; Disease Models, Animal ; Endocannabinoid ; Endocannabinoids - metabolism ; Endocannabinoids - physiology ; Female ; Glia ; Gliosis ; Inflammation ; Inflammation Mediators - metabolism ; Internal Medicine ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Targeted Therapy ; Neurogenic Inflammation - etiology ; Neurogenic Inflammation - genetics ; Neurology ; Plaque, Amyloid ; Receptors, Cannabinoid - metabolism ; Receptors, Cannabinoid - physiology ; Spatial Memory</subject><ispartof>Neurobiology of aging, 2015-11, Vol.36 (11), p.3008-3019</ispartof><rights>Elsevier Inc.</rights><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c565t-7ca53ce4a0375641d409ba830387135ef6ad33174c09ac80bcff6418156d31b3</citedby><cites>FETCH-LOGICAL-c565t-7ca53ce4a0375641d409ba830387135ef6ad33174c09ac80bcff6418156d31b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neurobiolaging.2015.08.003$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26362942$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vázquez, Carmen</creatorcontrib><creatorcontrib>Tolón, Rosa M</creatorcontrib><creatorcontrib>Grande, M. Teresa</creatorcontrib><creatorcontrib>Caraza, Marina</creatorcontrib><creatorcontrib>Moreno, Marta</creatorcontrib><creatorcontrib>Koester, Erin C</creatorcontrib><creatorcontrib>Villaescusa, Borja</creatorcontrib><creatorcontrib>Ruiz-Valdepeñas, Lourdes</creatorcontrib><creatorcontrib>Fernández-Sánchez, Francisco Javier</creatorcontrib><creatorcontrib>Cravatt, Benjamin F</creatorcontrib><creatorcontrib>Hillard, Cecilia J</creatorcontrib><creatorcontrib>Romero, Julián</creatorcontrib><title>Endocannabinoid regulation of amyloid-induced neuroinflammation</title><title>Neurobiology of aging</title><addtitle>Neurobiol Aging</addtitle><description>Abstract The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer's disease (AD). We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide-degrading enzyme in a mouse model of AD (5xFAD). Pharmacologic inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines and also on the cognitive impairment, plaque deposition, and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1 mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques, and gliosis. These data reinforce the notion of a role for the EC system in neuroinflammation and open new perspectives on the relevance of modulating EC levels in the inflammed brain.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - genetics</subject><subject>Amidohydrolases - genetics</subject><subject>Amidohydrolases - metabolism</subject><subject>Amidohydrolases - physiology</subject><subject>Amyloid</subject><subject>Amyloid - metabolism</subject><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Endocannabinoid</subject><subject>Endocannabinoids - metabolism</subject><subject>Endocannabinoids - physiology</subject><subject>Female</subject><subject>Glia</subject><subject>Gliosis</subject><subject>Inflammation</subject><subject>Inflammation Mediators - metabolism</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Molecular Targeted Therapy</subject><subject>Neurogenic Inflammation - etiology</subject><subject>Neurogenic Inflammation - genetics</subject><subject>Neurology</subject><subject>Plaque, Amyloid</subject><subject>Receptors, Cannabinoid - metabolism</subject><subject>Receptors, Cannabinoid - physiology</subject><subject>Spatial Memory</subject><issn>0197-4580</issn><issn>1558-1497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1r3DAQhkVpabZJ_0LZQw-92JmxvmwoLSUkTSDQQ3IXsiQv2spSKq0D---rzaaF9pTTwPDMvMwzhHxEaBFQnG_b6JacRp-C3vi4aTtA3kLfAtBXZIWc9w2yQb4mK8BBNoz3cELelbIFAMmkeEtOOkFFN7BuRb5eRpuMjlGPPiZv19ltlqB3PsV1mtZ63ofabXy0i3F2_RTt4xT0PD9BZ-TNpENx75_rKbm_ury_uG5uf3y_ufh22xgu-K6RRnNqHNNAJRcMLYNh1D0F2kuk3E1CW0pRMgODNj2MZpoq1iMXluJIT8mn49qHnH4truzU7ItxIejo0lIUyo5K0VHEin4-oianUrKb1EP2s857haAOBtVW_WtQHQwq6FU1WMc_PCct4-zs3-E_yipwdQRcPffRu6yK8S5WOz47s1M2-ZcmfflvkQk-eqPDT7d3ZZuWHKtShap0CtTd4ZuHZyIHYMg4_Q08i5_I</recordid><startdate>20151101</startdate><enddate>20151101</enddate><creator>Vázquez, Carmen</creator><creator>Tolón, Rosa M</creator><creator>Grande, M. Teresa</creator><creator>Caraza, Marina</creator><creator>Moreno, Marta</creator><creator>Koester, Erin C</creator><creator>Villaescusa, Borja</creator><creator>Ruiz-Valdepeñas, Lourdes</creator><creator>Fernández-Sánchez, Francisco Javier</creator><creator>Cravatt, Benjamin F</creator><creator>Hillard, Cecilia J</creator><creator>Romero, Julián</creator><general>Elsevier Inc</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></search><sort><creationdate>20151101</creationdate><title>Endocannabinoid regulation of amyloid-induced neuroinflammation</title><author>Vázquez, Carmen ; Tolón, Rosa M ; Grande, M. Teresa ; Caraza, Marina ; Moreno, Marta ; Koester, Erin C ; Villaescusa, Borja ; Ruiz-Valdepeñas, Lourdes ; Fernández-Sánchez, Francisco Javier ; Cravatt, Benjamin F ; Hillard, Cecilia J ; Romero, Julián</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c565t-7ca53ce4a0375641d409ba830387135ef6ad33174c09ac80bcff6418156d31b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - genetics</topic><topic>Amidohydrolases - genetics</topic><topic>Amidohydrolases - metabolism</topic><topic>Amidohydrolases - physiology</topic><topic>Amyloid</topic><topic>Amyloid - metabolism</topic><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Endocannabinoid</topic><topic>Endocannabinoids - metabolism</topic><topic>Endocannabinoids - physiology</topic><topic>Female</topic><topic>Glia</topic><topic>Gliosis</topic><topic>Inflammation</topic><topic>Inflammation Mediators - metabolism</topic><topic>Internal Medicine</topic><topic>Male</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Molecular Targeted Therapy</topic><topic>Neurogenic Inflammation - etiology</topic><topic>Neurogenic Inflammation - genetics</topic><topic>Neurology</topic><topic>Plaque, Amyloid</topic><topic>Receptors, Cannabinoid - metabolism</topic><topic>Receptors, Cannabinoid - physiology</topic><topic>Spatial Memory</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vázquez, Carmen</creatorcontrib><creatorcontrib>Tolón, Rosa M</creatorcontrib><creatorcontrib>Grande, M. 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We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide-degrading enzyme in a mouse model of AD (5xFAD). Pharmacologic inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines and also on the cognitive impairment, plaque deposition, and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1 mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques, and gliosis. 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| subjects | Alzheimer Disease - drug therapy Alzheimer Disease - genetics Amidohydrolases - genetics Amidohydrolases - metabolism Amidohydrolases - physiology Amyloid Amyloid - metabolism Animals Disease Models, Animal Endocannabinoid Endocannabinoids - metabolism Endocannabinoids - physiology Female Glia Gliosis Inflammation Inflammation Mediators - metabolism Internal Medicine Male Mice, Inbred C57BL Mice, Transgenic Molecular Targeted Therapy Neurogenic Inflammation - etiology Neurogenic Inflammation - genetics Neurology Plaque, Amyloid Receptors, Cannabinoid - metabolism Receptors, Cannabinoid - physiology Spatial Memory |
| title | Endocannabinoid regulation of amyloid-induced neuroinflammation |
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