Home › Research › Inflammation and the immune system
MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer’s disease model
Haishan Jiao, Yi‐Jun Ge, Liang-Yu Huang, Ying Liu, Bang‐Sheng Wu, Piaopiao Lian, Yizhe Hao, Shanshan Han et al.. Molecular Neurodegeneration, 2025-08-28
Topic: Brain proteins, microglia and lab models
We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures. Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Jiao, H., Ge, Y., Huang, L.-Y., Liu, Y., Wu, B., Lian, P., et al. (2025). MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer’s disease model. Molecular Neurodegeneration. https://doi.org/10.1186/s13024-025-00887-0
Vancouver
Jiao H, Ge Y, Huang L.-Y, Liu Y, Wu B, Lian P, et al. MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer’s disease model. Molecular Neurodegeneration. 2025. doi:10.1186/s13024-025-00887-0. PMID: 40877951.
BibTeX
@article{jiao2025-40877951,
author = {Jiao, Haishan and Ge, Yi‐Jun and Huang, Liang-Yu and Liu, Ying and Wu, Bang‐Sheng and Lian, Piaopiao and Hao, Yizhe and Han, Shanshan and others},
title = {{MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer’s disease model}},
journal = {Molecular Neurodegeneration},
year = {2025},
doi = {10.1186/s13024-025-00887-0},
pmid = {40877951},
url = {https://doi.org/10.1186/s13024-025-00887-0}
}
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.
Key findings
- We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid.
- Protective variant of MS4A6A is associated with elevated expression of the gene.
- Deficient Ms4a6d led to reduced amyloid clearance in the brain.
- Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia.
- In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage.
Why it matters
In APP/PS1 mice, lack of Ms4a6d reduced microglial clearance of amyloid, increased plaque burden and synaptic damage, and worsened inflammation, while overexpressing MS4A6A in human microglia reduced inflammation. The authors suggest boosting MS4A6A could be an effective treatment, but this is based on mouse and cell studies and has not been tested in patients.
Study details
- Participants734,121
- Evidence strengthModerate
How this study scored 51/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular Neurodegeneration) |
| Journal's citation record | 2 / 4 | Molecular Neurodegeneration: journal h-index 164 (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 | 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 | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 4 / 4 | 734,121 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 12 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 6.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 12 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Jin‐Tai Yu: h-index 94 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Fudan University: institution h-index 954 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40877951) |
| Free to read | 2 / 2 | Free to read |
| Total | 51 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s13024-025-00887-0
- PubMed: 40877951
- Original source →
- Free full text: Molecular Neurodegeneration →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 34.
Related studies in Inflammation and the immune system
Also tagged “amyloid-beta”
1,339 studies in the library carry the topic tag “amyloid-beta”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.