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| Status |
Public on Apr 26, 2024 |
| Title |
Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Microglia play important roles in maintaining brain homeostasis. The discovery of genetic variants in the genes encoding 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 microglial proteins are poorly conserved across species, and this hampered the development of APOE and TREM2 targeting therapeutic strategies. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs). In this study, we identified ASOs that selectively and potently reduce human APOE and TREM2 levels in human myeloid cells including iPSC-derived microglia. We demonstrated that a single bolus delivery of the ASOs in the mouse cerebrospinal fluid (CSF) is sufficient for the ASO to be pharmacologically active and modify the phenotype of xenografted human microglia throughout the mouse brain for at least 4 weeks. This study is the first proof-of-concept that the expression of microglial genes can be modulated using ASOs in a dose-dependent manner in order to manipulate human microglia phenotypes in vivo, and demonstrates the utility of these ASOs both as research and therapeutic tools to modulate neuroinflammation.
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| Overall design |
Bulk RNA sequencing on FACS-sorted CD11b+/hCD45+ xenotransplanted human microglia, examining App-NL-G-F mice (xenotrasplanted with human-embrionic-stem-cell-derived microglia) treated for 1 or 4 weeks with APOE- and TREM2-targeting antisense oligonucleotides compared to vehicle treatment, at 6-7 month of age (6 groups in total; 4 mice per experimental group).
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| Contributor(s) |
Vandermeulen L, Geric I, Kreir M, Lu A, Nonneman A, Wolfs L, Policarpo R, Fattorelli N, De Bondt A, Van Den Wyngaert I, Fiers M, De Strooper B, d’Ydewalle C, Mancuso R |
| Citation(s) |
38654375 |
| Submission date |
Dec 02, 2022 |
| Last update date |
Apr 26, 2024 |
| Contact name |
Ivana Geric |
| E-mail(s) |
ivana.geric@kuleuven.be
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| Organization name |
KU Leuven, Department of Neurosciences
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| Street address |
O&N4 Herestraat 49,
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| City |
Leuven |
| ZIP/Postal code |
3000 |
| Country |
Belgium |
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| Platforms (1) |
| GPL31277 |
DNBSEQ-G400 (Homo sapiens; Mus musculus) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA907839 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE219284_counts.txt.gz |
9.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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