Home › Research › Inflammation and the immune system
P2RX7 modulates the function of human microglia-like cells and mediates the association of IL18 with Alzheimer's disease traits
Kelsey S. Heavener, Kirstin A. Tamucci, Annie Lee, Khushbu Kabra, Zena K. Chatila, Maedot Yidenk, David Bennett, Badri Narayan Vardarajan et al.. Neurobiology of Disease, 2025-09-23
Topic: Brain proteins, microglia and lab models
The immune system plays a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades, and its expression is upregulated in Alzheimer's disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta (Aβ) plaques in the brain. Despite evidence linking P2RX7 to AD, the mechanisms by which it shapes microglial responses and contributes to AD remain poorly defined. Here, we utilize a human monocyte-derived microglia-like cell model (MDMi) to interrogate P2RX7 activation and downstream consequences on microglial function. Specifically, we measured IL1β and IL18 production and Aβ1-42 uptake following ATP-induced P2RX7 activation. Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression, which is blocked with the A740003 P2RX7 antagonist. Elevated extracellular ATP also impaired Aβ1-42 uptake, an effect reversed by P2RX7 inhibition with A740003. In addition, pretreatment of MDMi with IL-1Ra limited ATP-driven IL1β and IL18 gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Critically, analysis of postmortem human brain revealed that P2RX7 expression significantly mediated the association between IL18, but not IL1β, and multiple AD traits, including amyloid load, tau tangle density, global AD pathology burden, cortical and neocortical Lewy bodies, cognitive decline, and clinical dementia. Consistent with these findings, in our MDMi model, P2RX7 gene expression correlated with IL18 but not IL1β. Together, these findings highlight P2RX7 as a critical integrator of extracellular danger signals and microglial immune function, underscoring its potential as a therapeutic target in neurodegeneration.
Key findings
- Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression, which is blocked with the A740003 P2RX7 antagonist.
- Critically, analysis of postmortem human brain revealed that P2RX7 expression significantly mediated the association between IL18, but not IL1β, and multiple AD traits, including amyloid load, tau tangle density, global AD pathology burden, cortical and neocortical Lewy bodies, cognitive decline, and clinical dementia.
- Consistent with these findings, in our MDMi model, P2RX7 gene expression correlated with IL18 but not IL1β.
- Together, these findings highlight P2RX7 as a critical integrator of extracellular danger signals and microglial immune function, underscoring its potential as a therapeutic target in neurodegeneration.
Why it matters
In human microglia-like cells, blocking P2RX7 reduced inflammatory cytokine expression and restored amyloid beta uptake, and P2RX7 expression mediated the link between IL18 and several Alzheimer's traits in postmortem brain. This is laboratory and tissue research, so it does not yet show that P2RX7-targeting drugs treat Alzheimer's disease in patients.
Study details
- Evidence strengthLow
How this study scored 38/100
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 (Neurobiology of Disease) |
| Journal's citation record | 2 / 4 | Neurobiology of Disease: journal h-index 225 (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 | 4 / 5 | 2025 — within 3 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 | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.3× 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 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Elizabeth M. Bradshaw: h-index 33 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Columbia University: institution h-index 1,824 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40987420) |
| Free to read | 2 / 2 | Free to read |
| Total | 38 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/j.nbd.2025.107106
- PubMed: 40987420
- Original source →
- Free full text: Neurobiology of Disease →
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
Heavener, K. S., Tamucci, K. A., Lee, A., Kabra, K., Chatila, Z. K., Yidenk, M., et al. (2025). P2RX7 modulates the function of human microglia-like cells and mediates the association of IL18 with Alzheimer's disease traits. Neurobiology of Disease. https://doi.org/10.1016/j.nbd.2025.107106
Vancouver
Heavener KS, Tamucci KA, Lee A, Kabra K, Chatila ZK, Yidenk M, et al. P2RX7 modulates the function of human microglia-like cells and mediates the association of IL18 with Alzheimer's disease traits. Neurobiology of Disease. 2025. doi:10.1016/j.nbd.2025.107106. PMID: 40987420.
BibTeX
@article{heavener2025-40987420,
author = {Heavener, Kelsey S. and Tamucci, Kirstin A. and Lee, Annie and Kabra, Khushbu and Chatila, Zena K. and Yidenk, Maedot and Bennett, David and Vardarajan, Badri Narayan and others},
title = {{P2RX7 modulates the function of human microglia-like cells and mediates the association of IL18 with Alzheimer's disease traits}},
journal = {Neurobiology of Disease},
year = {2025},
doi = {10.1016/j.nbd.2025.107106},
pmid = {40987420},
url = {https://doi.org/10.1016/j.nbd.2025.107106}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.