Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome
Microglia are brain-resident immune cells and regulate mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by a supernumerary chromosome 21, containing also genes related to the immune system. In the hippocampus of t...
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| Veröffentlicht in: | Neuron (Cambridge, Mass.) Mass.), 2020-12, Vol.108 (5), p.887-904.e12 |
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| creator | Pinto, Bruno Morelli, Giovanni Rastogi, Mohit Savardi, Annalisa Fumagalli, Amos Petretto, Andrea Bartolucci, Martina Varea, Emilio Catelani, Tiziano Contestabile, Andrea Perlini, Laura E. Cancedda, Laura |
| description | Microglia are brain-resident immune cells and regulate mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by a supernumerary chromosome 21, containing also genes related to the immune system. In the hippocampus of the Dp(16) mouse model of DS and DS individuals, we found activated microglia, as assessed by their morphology; activation markers; and, for DS mice, electrophysiological profile. Accordingly, we found increased pro-inflammatory cytokine levels and altered interferon signaling in Dp(16) hippocampi. DS mice also showed decreased spine density and activity of hippocampal neurons and hippocampus-dependent cognitive behavioral deficits. Depletion of defective microglia or treatment with a commonly used anti-inflammatory drug rescued the neuronal spine and activity impairments and cognitive deficits in juvenile Dp(16) mice. Our results suggest an involvement of microglia in Dp(16)-mouse cognitive deficits and identify a new potential therapeutic approach for cognitive disabilities in DS individuals.
[Display omitted]
•DS mice display microglia alterations and cognitive impairment•Depletion of microglia rescues cognitive impairment in DS mice•Acetaminophen treatment rescues microglia and cognitive impairments in DS mice•Brain samples of DS people recapitulate microglia alterations observed in DS mice
Pinto, Morelli et al. identify a critical role for activated microglia in cognitive impairments of Down syndrome mouse models that can be ameliorated by either depleting microglia or using anti-inflammatory drugs to reduce microglia activation. In this work, microglia activation is also revealed in brains of people with Down syndrome. |
| doi_str_mv | 10.1016/j.neuron.2020.09.010 |
| format | Article |
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[Display omitted]
•DS mice display microglia alterations and cognitive impairment•Depletion of microglia rescues cognitive impairment in DS mice•Acetaminophen treatment rescues microglia and cognitive impairments in DS mice•Brain samples of DS people recapitulate microglia alterations observed in DS mice
Pinto, Morelli et al. identify a critical role for activated microglia in cognitive impairments of Down syndrome mouse models that can be ameliorated by either depleting microglia or using anti-inflammatory drugs to reduce microglia activation. In this work, microglia activation is also revealed in brains of people with Down syndrome.</description><identifier>ISSN: 0896-6273</identifier><identifier>EISSN: 1097-4199</identifier><identifier>DOI: 10.1016/j.neuron.2020.09.010</identifier><identifier>PMID: 33027640</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>acetaminophen ; Adult ; Age Factors ; Aminopyridines - pharmacology ; Aminopyridines - therapeutic use ; Animals ; Anti-inflammatory agents ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ; Brain ; Chromosome 21 ; Cognition - drug effects ; Cognition - physiology ; Cognitive ability ; cognitive defects ; Cytokines ; dendritic spines ; Disease Models, Animal ; Down syndrome ; Down Syndrome - drug therapy ; Down Syndrome - genetics ; Down Syndrome - physiopathology ; Down's syndrome ; Female ; Hippocampus ; Hippocampus - drug effects ; Hippocampus - physiopathology ; Humans ; Immune system ; Immunology ; Inflammation ; Intellectual disabilities ; Interferon ; Investigations ; Juveniles ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia ; Microglia - drug effects ; Microglia - physiology ; Morphology ; neurodevelopmental disorders ; neuroinflammation ; Proteins ; proteomics ; Pyrroles - pharmacology ; Pyrroles - therapeutic use ; Rodents ; Supernumerary ; Ts65Dn</subject><ispartof>Neuron (Cambridge, Mass.), 2020-12, Vol.108 (5), p.887-904.e12</ispartof><rights>2020 The Authors</rights><rights>Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2020. The Authors</rights><rights>2020 The Authors 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-dc7f1a0da43fbf486059055999bde9861c3046bdf9d8b7f369ad0e645dc9dcfb3</citedby><cites>FETCH-LOGICAL-c491t-dc7f1a0da43fbf486059055999bde9861c3046bdf9d8b7f369ad0e645dc9dcfb3</cites><orcidid>0000-0002-4002-9049 ; 0000-0001-5289-4219 ; 0000-0002-1171-8048 ; 0000-0002-1996-2870 ; 0000-0002-3790-5749 ; 0000-0002-5417-4722 ; 0000-0001-5905-735X ; 0000-0001-7811-8517 ; 0000-0002-9781-5999</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neuron.2020.09.010$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33027640$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pinto, Bruno</creatorcontrib><creatorcontrib>Morelli, Giovanni</creatorcontrib><creatorcontrib>Rastogi, Mohit</creatorcontrib><creatorcontrib>Savardi, Annalisa</creatorcontrib><creatorcontrib>Fumagalli, Amos</creatorcontrib><creatorcontrib>Petretto, Andrea</creatorcontrib><creatorcontrib>Bartolucci, Martina</creatorcontrib><creatorcontrib>Varea, Emilio</creatorcontrib><creatorcontrib>Catelani, Tiziano</creatorcontrib><creatorcontrib>Contestabile, Andrea</creatorcontrib><creatorcontrib>Perlini, Laura E.</creatorcontrib><creatorcontrib>Cancedda, Laura</creatorcontrib><title>Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome</title><title>Neuron (Cambridge, Mass.)</title><addtitle>Neuron</addtitle><description>Microglia are brain-resident immune cells and regulate mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by a supernumerary chromosome 21, containing also genes related to the immune system. In the hippocampus of the Dp(16) mouse model of DS and DS individuals, we found activated microglia, as assessed by their morphology; activation markers; and, for DS mice, electrophysiological profile. Accordingly, we found increased pro-inflammatory cytokine levels and altered interferon signaling in Dp(16) hippocampi. DS mice also showed decreased spine density and activity of hippocampal neurons and hippocampus-dependent cognitive behavioral deficits. Depletion of defective microglia or treatment with a commonly used anti-inflammatory drug rescued the neuronal spine and activity impairments and cognitive deficits in juvenile Dp(16) mice. Our results suggest an involvement of microglia in Dp(16)-mouse cognitive deficits and identify a new potential therapeutic approach for cognitive disabilities in DS individuals.
[Display omitted]
•DS mice display microglia alterations and cognitive impairment•Depletion of microglia rescues cognitive impairment in DS mice•Acetaminophen treatment rescues microglia and cognitive impairments in DS mice•Brain samples of DS people recapitulate microglia alterations observed in DS mice
Pinto, Morelli et al. identify a critical role for activated microglia in cognitive impairments of Down syndrome mouse models that can be ameliorated by either depleting microglia or using anti-inflammatory drugs to reduce microglia activation. In this work, microglia activation is also revealed in brains of people with Down syndrome.</description><subject>acetaminophen</subject><subject>Adult</subject><subject>Age Factors</subject><subject>Aminopyridines - pharmacology</subject><subject>Aminopyridines - therapeutic use</subject><subject>Animals</subject><subject>Anti-inflammatory agents</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</subject><subject>Brain</subject><subject>Chromosome 21</subject><subject>Cognition - drug effects</subject><subject>Cognition - physiology</subject><subject>Cognitive ability</subject><subject>cognitive defects</subject><subject>Cytokines</subject><subject>dendritic spines</subject><subject>Disease Models, Animal</subject><subject>Down syndrome</subject><subject>Down Syndrome - drug therapy</subject><subject>Down Syndrome - genetics</subject><subject>Down Syndrome - physiopathology</subject><subject>Down's syndrome</subject><subject>Female</subject><subject>Hippocampus</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - physiopathology</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Intellectual disabilities</subject><subject>Interferon</subject><subject>Investigations</subject><subject>Juveniles</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Microglia</subject><subject>Microglia - drug effects</subject><subject>Microglia - physiology</subject><subject>Morphology</subject><subject>neurodevelopmental disorders</subject><subject>neuroinflammation</subject><subject>Proteins</subject><subject>proteomics</subject><subject>Pyrroles - pharmacology</subject><subject>Pyrroles - therapeutic use</subject><subject>Rodents</subject><subject>Supernumerary</subject><subject>Ts65Dn</subject><issn>0896-6273</issn><issn>1097-4199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v1DAUjBCIbgv_ACFLXMoh4TlxnPiCVG35VKsiPs6WY79svUrsxU6Ceupfx6st5ePAxe_wZsZvZrLsGYWCAuWvtoXDOXhXlFBCAaIACg-yFQXR5IwK8TBbQSt4zsumOsqOY9wCUFYL-jg7qiooG85gld1-xqhn6zbkasGQKz3ZRU1oyKXVwW8Gq0hCTD5gJGu_cTbtkXzC0PswKqeRWEc-zgs6OyA5c3ZUQyS-J9M1kvPdKeUvyaWfI6bX4LDfnPsfjny5cSb4EZ9kj_rEwKd38yT79vbN1_X7_OLq3Yf12UWumaBTbnTTUwVGsarvetZyqAXUtRCiMyhaTnUFjHemF6btmr7iQhlAzmqjhdF9V51krw-6u7kb0Wh0U1CD3IV0cLiRXln598bZa7nxi2yaivMSksDpnUDw3-cUiRxt1DgMymHyJ0vGRMnLSjQJ-uIf6NbPwSV7CcVbzlhN24RiB1TKOcaA_f0xFOS-YbmVh4blvmEJQqaGE-35n0buSb8q_e0UU5yLxSCjtpiaMjagnqTx9v8__ASPmLtq</recordid><startdate>20201209</startdate><enddate>20201209</enddate><creator>Pinto, Bruno</creator><creator>Morelli, Giovanni</creator><creator>Rastogi, Mohit</creator><creator>Savardi, Annalisa</creator><creator>Fumagalli, Amos</creator><creator>Petretto, Andrea</creator><creator>Bartolucci, Martina</creator><creator>Varea, Emilio</creator><creator>Catelani, Tiziano</creator><creator>Contestabile, Andrea</creator><creator>Perlini, Laura E.</creator><creator>Cancedda, Laura</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><general>Cell Press</general><scope>6I.</scope><scope>AAFTH</scope><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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4002-9049</orcidid><orcidid>https://orcid.org/0000-0001-5289-4219</orcidid><orcidid>https://orcid.org/0000-0002-1171-8048</orcidid><orcidid>https://orcid.org/0000-0002-1996-2870</orcidid><orcidid>https://orcid.org/0000-0002-3790-5749</orcidid><orcidid>https://orcid.org/0000-0002-5417-4722</orcidid><orcidid>https://orcid.org/0000-0001-5905-735X</orcidid><orcidid>https://orcid.org/0000-0001-7811-8517</orcidid><orcidid>https://orcid.org/0000-0002-9781-5999</orcidid></search><sort><creationdate>20201209</creationdate><title>Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome</title><author>Pinto, Bruno ; Morelli, Giovanni ; Rastogi, Mohit ; Savardi, Annalisa ; Fumagalli, Amos ; Petretto, Andrea ; Bartolucci, Martina ; Varea, Emilio ; Catelani, Tiziano ; Contestabile, Andrea ; Perlini, Laura E. ; Cancedda, Laura</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-dc7f1a0da43fbf486059055999bde9861c3046bdf9d8b7f369ad0e645dc9dcfb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>acetaminophen</topic><topic>Adult</topic><topic>Age Factors</topic><topic>Aminopyridines - pharmacology</topic><topic>Aminopyridines - therapeutic use</topic><topic>Animals</topic><topic>Anti-inflammatory agents</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</topic><topic>Brain</topic><topic>Chromosome 21</topic><topic>Cognition - drug effects</topic><topic>Cognition - physiology</topic><topic>Cognitive ability</topic><topic>cognitive defects</topic><topic>Cytokines</topic><topic>dendritic spines</topic><topic>Disease Models, Animal</topic><topic>Down syndrome</topic><topic>Down Syndrome - drug therapy</topic><topic>Down Syndrome - genetics</topic><topic>Down Syndrome - physiopathology</topic><topic>Down's syndrome</topic><topic>Female</topic><topic>Hippocampus</topic><topic>Hippocampus - drug effects</topic><topic>Hippocampus - physiopathology</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Intellectual disabilities</topic><topic>Interferon</topic><topic>Investigations</topic><topic>Juveniles</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Microglia</topic><topic>Microglia - drug effects</topic><topic>Microglia - physiology</topic><topic>Morphology</topic><topic>neurodevelopmental disorders</topic><topic>neuroinflammation</topic><topic>Proteins</topic><topic>proteomics</topic><topic>Pyrroles - pharmacology</topic><topic>Pyrroles - therapeutic use</topic><topic>Rodents</topic><topic>Supernumerary</topic><topic>Ts65Dn</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pinto, Bruno</creatorcontrib><creatorcontrib>Morelli, Giovanni</creatorcontrib><creatorcontrib>Rastogi, Mohit</creatorcontrib><creatorcontrib>Savardi, Annalisa</creatorcontrib><creatorcontrib>Fumagalli, Amos</creatorcontrib><creatorcontrib>Petretto, Andrea</creatorcontrib><creatorcontrib>Bartolucci, Martina</creatorcontrib><creatorcontrib>Varea, Emilio</creatorcontrib><creatorcontrib>Catelani, Tiziano</creatorcontrib><creatorcontrib>Contestabile, Andrea</creatorcontrib><creatorcontrib>Perlini, Laura E.</creatorcontrib><creatorcontrib>Cancedda, Laura</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuron (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pinto, Bruno</au><au>Morelli, Giovanni</au><au>Rastogi, Mohit</au><au>Savardi, Annalisa</au><au>Fumagalli, Amos</au><au>Petretto, Andrea</au><au>Bartolucci, Martina</au><au>Varea, Emilio</au><au>Catelani, Tiziano</au><au>Contestabile, Andrea</au><au>Perlini, Laura E.</au><au>Cancedda, Laura</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome</atitle><jtitle>Neuron (Cambridge, Mass.)</jtitle><addtitle>Neuron</addtitle><date>2020-12-09</date><risdate>2020</risdate><volume>108</volume><issue>5</issue><spage>887</spage><epage>904.e12</epage><pages>887-904.e12</pages><issn>0896-6273</issn><eissn>1097-4199</eissn><abstract>Microglia are brain-resident immune cells and regulate mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by a supernumerary chromosome 21, containing also genes related to the immune system. In the hippocampus of the Dp(16) mouse model of DS and DS individuals, we found activated microglia, as assessed by their morphology; activation markers; and, for DS mice, electrophysiological profile. Accordingly, we found increased pro-inflammatory cytokine levels and altered interferon signaling in Dp(16) hippocampi. DS mice also showed decreased spine density and activity of hippocampal neurons and hippocampus-dependent cognitive behavioral deficits. Depletion of defective microglia or treatment with a commonly used anti-inflammatory drug rescued the neuronal spine and activity impairments and cognitive deficits in juvenile Dp(16) mice. Our results suggest an involvement of microglia in Dp(16)-mouse cognitive deficits and identify a new potential therapeutic approach for cognitive disabilities in DS individuals.
[Display omitted]
•DS mice display microglia alterations and cognitive impairment•Depletion of microglia rescues cognitive impairment in DS mice•Acetaminophen treatment rescues microglia and cognitive impairments in DS mice•Brain samples of DS people recapitulate microglia alterations observed in DS mice
Pinto, Morelli et al. identify a critical role for activated microglia in cognitive impairments of Down syndrome mouse models that can be ameliorated by either depleting microglia or using anti-inflammatory drugs to reduce microglia activation. In this work, microglia activation is also revealed in brains of people with Down syndrome.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33027640</pmid><doi>10.1016/j.neuron.2020.09.010</doi><orcidid>https://orcid.org/0000-0002-4002-9049</orcidid><orcidid>https://orcid.org/0000-0001-5289-4219</orcidid><orcidid>https://orcid.org/0000-0002-1171-8048</orcidid><orcidid>https://orcid.org/0000-0002-1996-2870</orcidid><orcidid>https://orcid.org/0000-0002-3790-5749</orcidid><orcidid>https://orcid.org/0000-0002-5417-4722</orcidid><orcidid>https://orcid.org/0000-0001-5905-735X</orcidid><orcidid>https://orcid.org/0000-0001-7811-8517</orcidid><orcidid>https://orcid.org/0000-0002-9781-5999</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | acetaminophen Adult Age Factors Aminopyridines - pharmacology Aminopyridines - therapeutic use Animals Anti-inflammatory agents Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Brain Chromosome 21 Cognition - drug effects Cognition - physiology Cognitive ability cognitive defects Cytokines dendritic spines Disease Models, Animal Down syndrome Down Syndrome - drug therapy Down Syndrome - genetics Down Syndrome - physiopathology Down's syndrome Female Hippocampus Hippocampus - drug effects Hippocampus - physiopathology Humans Immune system Immunology Inflammation Intellectual disabilities Interferon Investigations Juveniles Male Mice Mice, Inbred C57BL Mice, Transgenic Microglia Microglia - drug effects Microglia - physiology Morphology neurodevelopmental disorders neuroinflammation Proteins proteomics Pyrroles - pharmacology Pyrroles - therapeutic use Rodents Supernumerary Ts65Dn |
| title | Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome |
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