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The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, such as Apolipoprotein E (<jats:italic>APOE<\/jats:italic>) and triggering receptor expressed on myeloid cells 2 (<jats:italic>TREM2<\/jats:italic>), as the strongest risk factors for Alzheimer\u2019s disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of several microglial proteins are poorly conserved across species, which has hampered the development of strategies aiming to modulate the expression of specific microglial genes. One way to target <jats:italic>APOE<\/jats:italic> and <jats:italic>TREM2<\/jats:italic> is to modulate their expression using antisense oligonucleotides (ASOs).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In this study, we identified, produced, and tested novel, selective and potent ASOs for human <jats:italic>APOE<\/jats:italic> and <jats:italic>TREM2<\/jats:italic>. We used a combination of in vitro iPSC-microglia models, as well as microglial xenotransplanted mice to provide proof of activity in human microglial in vivo.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We proved their efficacy in human iPSC microglia in vitro, as well as their pharmacological activity in vivo in a xenografted microglia model. We demonstrate ASOs targeting human microglia can modify their transcriptional profile and their response to amyloid-\u03b2 plaques in vivo in a model of AD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study is the first proof-of-concept that human microglial can be modulated using ASOs in a dose-dependent manner to manipulate microglia phenotypes and response to neurodegeneration in vivo<jats:italic>.<\/jats:italic><\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13024-024-00725-9","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T02:01:51Z","timestamp":1713924111000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"19","author":[{"given":"Lina","family":"Vandermeulen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Geric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fumagalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Kreir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Nonneman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie","family":"Premereur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leen","family":"Wolfs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela","family":"Policarpo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Fattorelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"De Bondt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse","family":"Van Den Wyngaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bob","family":"Asselbergh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Fiers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"De Strooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"d\u2019Ydewalle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7046-3348","authenticated-orcid":false,"given":"Renzo","family":"Mancuso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,24]]},"reference":[{"key":"725_CR1","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1038\/ng.3916","volume":"49","author":"R Sims","year":"2017","unstructured":"Sims R, et al. 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