{"created":"2023-05-15T14:51:24.358339+00:00","id":70274,"links":{},"metadata":{"_buckets":{"deposit":"906bfaa9-a22a-4458-820a-d067865f8e6f"},"_deposit":{"created_by":1,"id":"70274","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"70274"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00070274","sets":["10:28"]},"author_link":["689951","689963","689957","689964","689948","689961","689962","689949","689965","689958","689952","689950","689953","689959","689956","689954","689960","689955","689947"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2010-10-08","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Neuropathological hallmarks of Alzheimer’s disease (AD) are composed of fibrillary aggregates of amyloid beta; peptide (Abeta)and tau proteins, and are mechanistically involved in the molecular etiology of this illness. Multiple lines of preclinical evidences have supported the potential utility of Abeta vaccines and other immunotherapeutic approaches to AD, while functional modulations of immunocompetent microglia by such treatments may also provoke deleterious proinflammatory signaling, which may accelerate neurotoxic processes induced by Abeta and tau depositions. In our previous assays of transgenic (Tg) mice modeling Abeta and tau pathologies, noticeable microgliosis with upregulation of 18-kDa translocator protein (TSPO) was triggered by unrecoverable neuronal injuries. Since TSPO can be visualized by positron emission tomographic (PET) imaging, this observation highlighted the significance of TSPO as a biomarker for toxic neuroinflammatory responses. Furthermore, immunohistochemical analyses suggested that TSPO may participate in the transition of microglial functions from neuroprotective to aggressive modes (Ji et al., J Neuroscience 2008). These indications led to the contention that chemical mediators released from microglia with high-level TSPO expression impede beneficial glial activities counteracting Abeta and tau toxicities. Here, we tested this possibility by assessing outcomes of implantations of microglial clones expressing TSPO at different levels into brains of amyloid precursor protein (APP) Tg mice with abundant Abeta deposits. PET investigations of amyloid and TSPO demonstrated that low, but not high TSPO expressor clones efficiently removed Abeta aggregates within one week of the implantation by inducing activation of resident microglia without increasing their TSPO levels. Subsequent comparison of cytokine profiles in these clones with an antibody array illustrated a dramatically enhanced secretion of monocyte chemotactic protein-1 (MCP-1) and several other chemokines in the TSPO-rich clone. In addition, MCP-1 was shown to bind to synthetic Abeta assemblies by in vitro surface plasmon resonance measurements, and colocalization of MCP1 with Abeta and tau lesions was observed in immunolabeling of postmortem AD brains with our original anti-human MCP-1 antibody, suggesting direct interaction between microglia-derived MCP-1 and core pathologies of AD. This finding also implies that blockade of MCP-1 signaling may fortify therapeutic effects of Abeta vaccination by directing microglia from detrimental to neuroprotective state. The feasibility of this strategy was verified by treating APP Tg mice with a combination of anti-Abeta and anti-MCP-1 antibodies, which resulted in enhanced, long-lasting reduction of Abeta and suppression of TSPO-positive gliosis as compared with anti-Abeta antibody alone. Moreover, treatment of lipopolysaccharide-stimulated microglial cultures with a TSPO ligand, PK11195, inhibited the secretion of several proinflammatory factors including MCP-1, justifying the use of TSPO modifiers for suppressing the neurotoxic inflammatory pathway. Taken together, the present results demonstrate that activation of microglial cells concurrent with TSPO upregulation impairs their proper functions against Abeta accumulation, and that pharmacological manipulations of MCP-1 and TSPO could serve for reversing their loss of beneficial functions and gain of neurotoxicities. Our imaging data have also proven the high performance of TSPO-PET in monitoring primary and adverse effects of anti-amyloid immunotherapies in living individuals.","subitem_description_type":"Abstract"}]},"item_10005_description_6":{"attribute_name":"会議概要（会議名, 開催地, 会期, 主催者等）","attribute_value_mlt":[{"subitem_description":"第29回内藤コンファレンス","subitem_description_type":"Other"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"metadata only access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_14cb"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"Ki, Hin"}],"nameIdentifiers":[{"nameIdentifier":"689947","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Maruyama, Masahiro"}],"nameIdentifiers":[{"nameIdentifier":"689948","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Hattori, Satoko"}],"nameIdentifiers":[{"nameIdentifier":"689949","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Maeda, Jun"}],"nameIdentifiers":[{"nameIdentifier":"689950","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ono, Maiko"}],"nameIdentifiers":[{"nameIdentifier":"689951","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Okauchi, Takashi"}],"nameIdentifiers":[{"nameIdentifier":"689952","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong"}],"nameIdentifiers":[{"nameIdentifier":"689953","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Higuchi, Makoto"}],"nameIdentifiers":[{"nameIdentifier":"689954","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Suhara, Tetsuya"}],"nameIdentifiers":[{"nameIdentifier":"689955","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"et.al"}],"nameIdentifiers":[{"nameIdentifier":"689956","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"季 斌","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689957","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"丸山 将浩","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689958","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"服部 聡子","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689959","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"前田 純","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689960","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"小野 麻衣子","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689961","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"岡内 隆","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689962","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"張 明栄","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689963","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"樋口 真人","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689964","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"須原 哲也","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"689965","nameIdentifierScheme":"WEKO"}]}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"conference object","resourceuri":"http://purl.org/coar/resource_type/c_c94f"}]},"item_title":"In vivo imaging and therapeutic modulations of microglial response to A-beta amyloidosis by interrupting deleterious chemokine signaling in a rodent model of Alzheimer's disease","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"In vivo imaging and therapeutic modulations of microglial response to A-beta amyloidosis by interrupting deleterious chemokine signaling in a rodent model of Alzheimer's disease"}]},"item_type_id":"10005","owner":"1","path":["28"],"pubdate":{"attribute_name":"公開日","attribute_value":"2010-10-12"},"publish_date":"2010-10-12","publish_status":"0","recid":"70274","relation_version_is_last":true,"title":["In vivo imaging and therapeutic modulations of microglial response to A-beta amyloidosis by interrupting deleterious chemokine signaling in a rodent model of Alzheimer's disease"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T20:04:50.958608+00:00"}