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Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer's disease
Chen MJ, Ramesha S, Weinstock LD, Gao T, Ping L, Xiao H, Dammer EB, Duong DD et al.. Journal of neuroscience research, 2021-03-17
Topic: Brain proteins, microglia and lab models
The importance of mitogen-activated protein kinase (MAPK) pathway signaling in regulating microglia-mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal-regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole-brain tissue from 5xFAD mice.
Key findings
- We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains.
- In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal-regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole-brain tissue from 5xFAD mice.
- The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid-β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ-mediated pro-inflammatory activation of microglia, although it was also partly important for constitutive microglial functions.
- Phospho-ERK was an upstream regulator of disease-associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology.
Why it matters
In a mouse model of Alzheimer's pathology and in postmortem human brain tissue, phosphorylated ERK was the most strongly increased signaling protein within microglia. This identifies a signaling pathway that may regulate microglial immune responses, but it is early research and not a tested treatment.
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Study details
- Evidence strengthLow
How this study scored 44/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of neuroscience research) |
| Journal's citation record | 2 / 4 | Journal of Neuroscience Research: journal h-index 222 (OpenAlex, 2026-10-29) |
| 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 | 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 | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 122 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 17.4 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 3 / 6 | Cited 6.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 3 / 4 | Cited 63 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Srikant Rangaraju: h-index 44 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Emory University: institution h-index 1,360 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33729626) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 44 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1002/jnr.24829
- PubMed: 33729626
- Original source →
- Free full text: bioRxiv (Cold Spring Harbor Laboratory) →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Chen, M. J., Ramesha, S., Weinstock, L. D., Gao, T., Ping, L., Xiao, H., et al. (2021). Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer's disease. Journal of neuroscience research. https://doi.org/10.1002/jnr.24829
Vancouver
Chen MJ, Ramesha S, Weinstock LD, Gao T, Ping L, Xiao H, et al. Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer's disease. Journal of neuroscience research. 2021. doi:10.1002/jnr.24829. PMID: 33729626.
BibTeX
@article{chen2021-33729626,
author = {Chen, M. J. and Ramesha, S. and Weinstock, L. D. and Gao, T. and Ping, L. and Xiao, H. and Dammer, E. B. and Duong, D. D. and others},
title = {{Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer's disease}},
journal = {Journal of neuroscience research},
year = {2021},
doi = {10.1002/jnr.24829},
pmid = {33729626},
url = {https://doi.org/10.1002/jnr.24829}
}
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