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CRISPR/dCas9-Dnmt3a-mediated targeted DNA methylation of APP rescues brain pathology in a mouse model of Alzheimer's disease
Park H, Shin J, Kim Y, Saito T, Saido TC, Kim J.. Translational neurodegeneration, 2022-09-15
Topic: Disease mechanisms in lab and animal studies
Background Aberrant DNA methylation patterns have been observed in neurodegenerative diseases, including Alzheimer's disease (AD), and dynamic changes in DNA methylation are closely associated with the onset and progression of these diseases. Particularly, hypomethylation of the amyloid precursor protein gene (APP) has been reported in patients with AD. Methods In this study, we used catalytically inactivated Cas9 (dCas9) fused with Dnmt3a for targeted DNA methylation of APP, and showed that the CRISPR/dCas9-Dnmt3a-mediated DNA methylation system could efficiently induce targeted DNA methylation of APP both in vivo and in vitro. Results We hypothesized that the targeted methylation of the APP promoter might rescue AD-related neuronal cell death by reducing APP mRNA expression. The cultured APP-KI mouse primary neurons exhibited an altered DNA-methylation pattern on the APP promoter after dCas9-Dnmt3a treatment. Likewise, the APP mRNA level was significantly reduced in the dCas9-Dnmt3a-treated wild-type and APP-KI mouse primary neurons. We also observed decreased amyloid-beta (Aβ) peptide level and Aβ42/40 ratio in the dCas9-Dnmt3a-treated APP-KI mouse neurons compared to the control APP-KI mouse neurons. In addition, neuronal cell death was significantly decreased in the dCas9-Dnmt3a-treated APP-KI mouse neurons. Furthermore, the in vivo methylation of APP in the brain via dCas9-Dnmt3a treatment altered Aβ plaques and attenuated cognitive and behavioral impairments in the APP-KI mouse model. Conclusions These results suggest that the targeted methylation of APP via dCas9-Dnmt3a treatment can be a potential therapeutic strategy for AD.
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APA 7th
Park, H., Shin, J., Kim, Y., Saito, T., Saido, T. C., & Kim, J. (2022). CRISPR/dCas9-Dnmt3a-mediated targeted DNA methylation of APP rescues brain pathology in a mouse model of Alzheimer's disease. Translational neurodegeneration. https://doi.org/10.1186/s40035-022-00314-0
Vancouver
Park H, Shin J, Kim Y, Saito T, Saido TC, Kim J. CRISPR/dCas9-Dnmt3a-mediated targeted DNA methylation of APP rescues brain pathology in a mouse model of Alzheimer's disease. Translational neurodegeneration. 2022. doi:10.1186/s40035-022-00314-0. PMID: 36109806.
BibTeX
@article{park2022-36109806,
author = {Park, H. and Shin, J. and Kim, Y. and Saito, T. and Saido, T. C. and Kim, J.},
title = {{CRISPR/dCas9-Dnmt3a-mediated targeted DNA methylation of APP rescues brain pathology in a mouse model of Alzheimer's disease}},
journal = {Translational neurodegeneration},
year = {2022},
doi = {10.1186/s40035-022-00314-0},
pmid = {36109806},
url = {https://doi.org/10.1186/s40035-022-00314-0}
}
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Key findings
- Background Aberrant DNA methylation patterns have been observed in neurodegenerative diseases, including Alzheimer's disease (AD), and dynamic changes in DNA methylation are closely associated with the onset and progression of these diseases.
- Methods In this study, we used catalytically inactivated Cas9 (dCas9) fused with Dnmt3a for targeted DNA methylation of APP, and showed that the CRISPR/dCas9-Dnmt3a-mediated DNA methylation system could efficiently induce targeted DNA methylation of APP both in vivo and in vitro.
- Results We hypothesized that the targeted methylation of the APP promoter might rescue AD-related neuronal cell death by reducing APP mRNA expression.
- Likewise, the APP mRNA level was significantly reduced in the dCas9-Dnmt3a-treated wild-type and APP-KI mouse primary neurons.
- We also observed decreased amyloid-beta (Aβ) peptide level and Aβ42/40 ratio in the dCas9-Dnmt3a-treated APP-KI mouse neurons compared to the control APP-KI mouse neurons.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Translational neurodegeneration) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mouse”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 36109806) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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