دورية أكاديمية
Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer’s disease
| العنوان: | Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer’s disease |
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| المؤلفون: | Lina Vandermeulen, Ivana Geric, Laura Fumagalli, Mohamed Kreir, Ashley Lu, Annelies Nonneman, Jessie Premereur, Leen Wolfs, Rafaela Policarpo, Nicola Fattorelli, An De Bondt, Ilse Van Den Wyngaert, Bob Asselbergh, Mark Fiers, Bart De Strooper, Constantin d’Ydewalle, Renzo Mancuso |
| المصدر: | Molecular Neurodegeneration, Vol 19, Iss 1, Pp 1-25 (2024) |
| بيانات النشر: | BMC, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Neurology. Diseases of the nervous system LCC:Geriatrics |
| مصطلحات موضوعية: | Microglia, Neuroinflammation, Alzheimer’s disease, Antisense oligonucleotide, TREM2, APOE, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6 |
| الوصف: | Abstract Background Microglia play important roles in maintaining brain homeostasis and neurodegeneration. The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, such as Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), as the strongest risk factors for Alzheimer’s 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 APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs). Methods In this study, we identified, produced, and tested novel, selective and potent ASOs for human APOE and TREM2. 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. Results 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-β plaques in vivo in a model of AD. Conclusions 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1750-1326 |
| Relation: | https://doaj.org/toc/1750-1326 |
| DOI: | 10.1186/s13024-024-00725-9 |
| URL الوصول: | https://doaj.org/article/5e41afed90e54039b14a1ba9aaa0716d |
| رقم الأكسشن: | edsdoj.5e41afed90e54039b14a1ba9aaa0716d |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 17501326 |
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| DOI: | 10.1186/s13024-024-00725-9 |