Evidence map›Paper›PMID 40987420›Full record

ArticleNeurobiology of disease2025

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 J Lee, Khushbu Kabra, Zena K Chatila, Maedot Yidenk, David A Bennett, Badri N Vardarajan, Elizabeth M Bradshaw

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurobiology of disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Kelsey S HeavenerDivision of Translational Neurobiology, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; The Carol and Gene Ludwig Center for Research on Neurodegeneration, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA.
Kirstin A TamucciDivision of Translational Neurobiology, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; The Carol and Gene Ludwig Center for Research on Neurodegeneration, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA.
Annie J LeeThe Carol and Gene Ludwig Center for Research on Neurodegeneration, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Khushbu KabraDivision of Translational Neurobiology, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; The Carol and Gene Ludwig Center for Research on Neurodegeneration, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA.
Zena K ChatilaDivision of Translational Neurobiology, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; The Carol and Gene Ludwig Center for Research on Neurodegeneration, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA.
Maedot YidenkDivision of Translational Neurobiology, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; The Carol and Gene Ludwig Center for Research on Neurodegeneration, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA.
David A BennettRush Alzheimer Disease Center, Rush University Medical Center, Chicago, IL, USA.
Badri N VardarajanThe Carol and Gene Ludwig Center for Research on Neurodegeneration, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Elizabeth M BradshawDivision of Translational Neurobiology, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; The Carol and Gene Ludwig Center for Research on Neurodegeneration, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA. Electronic address: emb2280@cumc.columbia.edu.

Funding

SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1M
EPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3M
Research Education CoreP30AG066462 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI PHILIP L DE JAGER · 2020 to 2026
$30.1M
Rush Alzheimer's Disease Research CenterP30AG072975 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI Lisa L Barnes, Julie A. Schneider · 2021 to 2026
$24.7M
RISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4M
Multi-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targetsU01AG061356 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2018 to 2022
$13.7M
Pathway discovery, validation and compound identification for Alzheimer's disease - SupplementU01AG046152 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2013 to 2017
$13.6M
Intersection of HSV-1 and microglial genetics in ADR01AG076018 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BRADSHAW, ELIZABETH M, ELYAMAN, WASSIM · 2021 to 2025
$3.8M
Convergence of myeloid susceptibility protein function in Alzheimer's diseaseRF1AG058852 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BRADSHAW, ELIZABETH M · 2018 to 2020
$2.9M
Investigating the convergence of AD genetics on lipid metabolism and microglia regulationR21AG073882 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI AREA GOMEZ, ESTELA, BRADSHAW, ELIZABETH M · 2021 to 2021
$431k
Genetic Association Between Alzheimer's Disease and Cardio-Cerebrovascular Risk FactorsK01AG084849 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Annie J Lee · 2024 to 2026
$377k
NIA NIH HHS K01 AG084849NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG066462NIA NIH HHS P30 AG072975NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG076018NIA NIH HHS R21 AG073882NIA NIH HHS RF1 AG058852NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356
6 · The paper itself

Abstract

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.

Indexed as

Alzheimer DiseaseInterleukin-18MicrogliaReceptors, Purinergic P2X7Amyloid beta-PeptidesBrainHumansAmyloid beta-PeptidesIL18 protein, humanInterleukin-18P2RX7 protein, humanReceptors, Purinergic P2X7Alzheimer's diseaseAmyloid-betaATPIL-1RaNeurodegenerationP2RX7

Identifiers

PMID40987420
PMCPMC12599179

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.