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Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222333 | GEO | 2026/01/02

REPOSITORIES: GEO

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Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia

Project description: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.

2024-04-26 | GSE219284 | GEO

Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia (TREM2 subset_GEO)

Project description: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 is sufficient for the ASO to be pharmacologically active and modify the phenotype of xenografted human microglia throughout the rodent 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.

2026-01-02 | GSE222332 | GEO

Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia (APOE subset_GEO)

Project description: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 is sufficient for the ASO to be pharmacologically active and modify the phenotype of xenografted human microglia throughout the rodent 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.

2026-01-02 | GSE222331 | GEO

Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia

Project description:Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia

| PRJNA907839 | ENA

Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia

Project description:Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia

| PRJNA919026 | ENA

Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia (APOE subset_GEO)

Project description:Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia (APOE subset_GEO)

| PRJNA919030 | ENA

Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia (TREM2 subset_GEO)

Project description:Alzheimer’s disease neuroinflammatory risk genes can be targeted with RNase-H active antisense oligonucleotides in human microglia (TREM2 subset_GEO)

| PRJNA919029 | ENA

Targeted Molecular Therapeutics for Parkinson's Disease: A Role for Antisense Oligonucleotides?

Project description: Not available

| S-EPMC9804368 | biostudies-literature

RNase H1-Dependent Antisense Oligonucleotides Are Robustly Active in Directing RNA Cleavage in Both the Cytoplasm and the Nucleus.

Project description:RNase H1-dependent antisense oligonucleotides (ASOs) are active in reducing levels of both cytoplasmic mRNAs and nuclear retained RNAs. Although ASO activity in the nucleus has been well demonstrated, the cytoplasmic activity of ASOs is less clear. Using kinetic and subcellular fractionation studies, we evaluated ASO activity in the cytoplasm. Upon transfection, ASOs targeting exonic regions rapidly reduced cytoplasmically enriched mRNAs, whereas an intron-targeting ASO that only degrades the nuclear pre-mRNA reduced mRNA levels at a slower rate, similar to normal mRNA decay. Importantly, some exon-targeting ASOs can rapidly and vigorously reduce mRNA levels without decreasing pre-mRNA levels, suggesting that pre-existing cytoplasmic mRNAs can be cleaved by RNase H1-ASO treatment. In addition, we expressed a cytoplasm-localized mutant 7SL RNA that contains a partial U16 small nucleolar RNA (snoRNA) sequence. Treatment with an ASO simultaneously reduced both the nuclear U16 snoRNA and the cytoplasmic 7SL mutant RNA as early as 30 min after transfection in an RNase H1-dependent manner. Both the 5' and 3' cleavage products of the 7SL mutant RNA were accumulated in the cytoplasm. Together, these results demonstrate that RNase H1-dependent ASOs are robustly active in both the cytoplasm and nucleus.

| S-EPMC5589097 | biostudies-literature

Translation can affect the antisense activity of RNase H1-dependent oligonucleotides targeting mRNAs.

Project description:RNase H1-dependent antisense oligonucleotides (ASOs) can degrade complementary RNAs in both the nucleus and the cytoplasm. Since cytoplasmic mRNAs are actively engaged in translation, ASO activity may thus be affected by translating ribosomes that scan the mRNAs. Here we show that mRNAs associated with ribosomes can be cleaved using ASOs and that translation can alter ASO activity. Translation inhibition tends to increase ASO activity when targeting the coding regions of efficiently translated mRNAs, but not nuclear non-coding RNAs or less efficiently translated mRNAs. Increasing the level of RNase H1 protein eliminated the enhancing effects of translation inhibition on ASO activity, suggesting that RNase H1 recruitment to ASO/mRNA heteroduplexes is a rate limiting step and that translating ribosomes can inhibit RNase H1 recruitment. Consistently, ASO activity was not increased by translation inhibition when targeting the 3' UTRs, independent of the translation efficiency of the mRNAs. Contrarily, the activity of 3' UTR-targeting ASOs tended to be reduced upon translation inhibition, likely due to decreased accessibility. These results indicate that ASO activity can be affected by the translation process, and the findings also provide important information toward helping better ASO drug design.

| S-EPMC5758896 | biostudies-literature

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