Ms4a4a loss preferentially remodels microglia with limited, compartment-specific effects across central and peripheral immune compartments in 5xFAD mice
Danhash EP, Verbeck AC, Iyer AK, Karch CM.. bioRxiv, 2026-10-27
Topic: Inflammation, microglia and astrocytes
Background Genome-wide association studies have identified the MS4A locus as a major modifier of Alzheimer’s disease (AD) risk and resilience. MS4A4A is enriched in microglia, and we previously demonstrated that loss of Ms4a4a reduces amyloid plaque pathology and attenuates amyloid-associated tau spreading. However, MS4A4A is also expressed in peripheral myeloid populations, raising the possibility that its effects extend beyond brain-resident microglia. Here, we sought to define how constitutive Ms4a4a loss alters immune populations across central nervous system (CNS), CNS-border, and peripheral compartments in the context of amyloid pathology. Methods We performed multicompartment immune profiling by flow cytometry in 5xFAD Ms4a4a wild-type and 5xFAD Ms4a4a -deficient mice. Myeloid and lymphoid populations were characterized in the brain, dural meninges, skull bone marrow, tibial bone marrow, and spleen. Results Ms4a4a loss produced its strongest immune effects in brain microglia. 5xFAD Ms4a4a -deficient mice exhibited increased microglial abundance, increased frequency and expression of CD86, increased MHC class II expression intensity, and enrichment of CXCR4-high microglia, whereas P2RY12 and TREM2 were unchanged. Brain macrophages showed increased MHC class II expression, whereas conventional dendritic cells (cDCs) in the brain showed reduced MHC class II expression, with limited changes in other infiltrating immune populations. Immune composition in the dura and skull bone marrow was largely preserved, although MHC class II expression was increased in skull bone marrow cDCs. Peripheral immune composition in tibial bone marrow and spleen was similarly preserved, with selective increases in M2-like macrophages in tibial bone marrow and splenic CD8 T-cell frequency. Conclusions These findings identify microglia as the immune population most strongly remodeled by Ms4a4a loss in the setting of amyloid pathology. Constitutive Ms4a4a deficiency does not produce broad systemic immune remodeling but instead preferentially alters microglial state, accompanied by more limited, cell type- and tissue-specific effects across other central and peripheral immune compartments. These findings establish MS4A4A as a context-dependent regulator of immune responses to AD pathology with particularly prominent effects on microglia.
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APA 7th
Danhash, E. P., Verbeck, A. C., Iyer, A. K., & Karch, C. M. (2026). Ms4a4a loss preferentially remodels microglia with limited, compartment-specific effects across central and peripheral immune compartments in 5xFAD mice. bioRxiv. https://doi.org/10.64898/2026.10.26.762005
Vancouver
Danhash EP, Verbeck AC, Iyer AK, Karch CM. Ms4a4a loss preferentially remodels microglia with limited, compartment-specific effects across central and peripheral immune compartments in 5xFAD mice. bioRxiv. 2026. doi:10.64898/2026.10.26.762005.
BibTeX
@article{danhash2026-f606cf98,
author = {Danhash, E. P. and Verbeck, A. C. and Iyer, A. K. and Karch, C. M.},
title = {{Ms4a4a loss preferentially remodels microglia with limited, compartment-specific effects across central and peripheral immune compartments in 5xFAD mice}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.26.762005},
url = {https://doi.org/10.64898/2026.10.26.762005}
}
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Key findings
- MS4A4A is enriched in microglia, and we previously demonstrated that loss of Ms4a4a reduces amyloid plaque pathology and attenuates amyloid-associated tau spreading.
- Results Ms4a4a loss produced its strongest immune effects in brain microglia. 5xFAD Ms4a4a -deficient mice exhibited increased microglial abundance, increased frequency and expression of CD86, increased MHC class II expression intensity, and enrichment of CXCR4-high microglia, whereas P2RY12 and TREM2 were unchanged.
- Conclusions These findings identify microglia as the immune population most strongly remodeled by Ms4a4a loss in the setting of amyloid pathology.
- These findings establish MS4A4A as a context-dependent regulator of immune responses to AD pathology with particularly prominent effects on microglia.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on 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 multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 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 “5xfad”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation 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 |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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