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Multimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease
Xu J, Zhang P, Huang Y, Zhou Y, Hou Y, Bekris LM, Lathia J, Chiang CW et al.. Genome research, 2021-02-24
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
Because disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer's disease (AD), we systematically identified molecular networks between DAM and DAA to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metabolite-enzyme associations, the human protein-protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1 , MAPK14 , and CSF1R ) and DAA (i.e., NFKB1 , FOS , and JUN ) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1 ). We identify shared immune pathways between DAM and DAA, including Th17 cell differentiation and chemokine signaling. Last, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA. Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.83-0.89, P < 1.0 × 10 -8 ). Propensity score-stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR = 0.74, 95% CI 0.68-0.81, P < 1.0 × 10 -8 ) compared to fluticasone after adjusting age, gender, and disease comorbidities. In summary, we present a network-based, multimodal methodology for single-cell/nucleus genomics-informed drug discovery and have identified fluticasone and mometasone as potential treatments in AD.
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APA 7th
Xu, J., Zhang, P., Huang, Y., Zhou, Y., Hou, Y., Bekris, L. M., et al. (2021). Multimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease. Genome research. https://doi.org/10.1101/gr.272484.120
Vancouver
Xu J, Zhang P, Huang Y, Zhou Y, Hou Y, Bekris LM, et al. Multimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease. Genome research. 2021. doi:10.1101/gr.272484.120. PMID: 33627474.
BibTeX
@article{xu2021-33627474,
author = {Xu, J. and Zhang, P. and Huang, Y. and Zhou, Y. and Hou, Y. and Bekris, L. M. and Lathia, J. and Chiang, C. W. and others},
title = {{Multimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease}},
journal = {Genome research},
year = {2021},
doi = {10.1101/gr.272484.120},
pmid = {33627474},
url = {https://doi.org/10.1101/gr.272484.120}
}
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Key findings
- Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1 , MAPK14 , and CSF1R ) and DAA (i.e., NFKB1 , FOS , and JUN ) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1 ).
- Last, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA.
- Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.83-0.89, P < 1.0 × 10 -8 ).
- Propensity score-stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR = 0.74, 95% CI 0.68-0.81, P < 1.0 × 10 -8 ) compared to fluticasone after adjusting age, gender, and disease comorbidities.
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Study details
- Study designcohort study
- Effect sizeHR = 0.74
- Evidence strengthModerate
How this study scored 64/100
Published in a peer-reviewed journal, and it is a cohort study following people over time. Scored zero for sample size, studied in people 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 37 of the 58 points we could judge it on, which is 64 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Genome research) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — 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 | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| 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 33627474) |
| Free to read | 2 / 2 | Free to read |
| Points | 37 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 37 of the 58 points we could judge it on is 64 out of 100. |
| Total | 64 / 100 | — |
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