Summary: Researchers at the University of California, San Francisco (UCSF) have identified a receptor, ADGRG1, that enables microglia — the brain’s resident immune cells — to recognize, engulf, and digest toxic amyloid-beta plaques associated with Alzheimer’s disease. Laboratory models lacking this receptor showed accelerated plaque accumulation, neuronal loss, and memory deficits, while analyses of human brain samples linked higher ADGRG1 expression in microglia with milder Alzheimer’s symptoms. The finding points to a new therapeutic approach focused on boosting microglial plaque clearance to slow or prevent disease progression.
Alzheimer’s disease is driven in part by the aggregation of amyloid-beta protein into extracellular plaques that disrupt neural networks. Microglia play a central role in maintaining brain health by clearing abnormal proteins and cellular debris, but their effectiveness varies between individuals. This study shows that ADGRG1, an adhesion G protein-coupled receptor (aGPCR) expressed selectively in yolk-sac–derived microglia, is a key molecular switch that promotes a protective, plaque-clearing microglial state.
Key Facts:
- Protective receptor: ADGRG1 enables microglia to digest amyloid-beta plaques, supporting brain clearance mechanisms.
- Clinical correlation: Human brain data reanalysis found that people who died with milder Alzheimer’s had microglia enriched for ADGRG1, while severe cases showed low ADGRG1 and more plaque accumulation.
- Therapeutic potential: ADGRG1 belongs to the GPCR family, which are well-established and druggable targets, making it a promising candidate for therapeutic development.
Using the 5xFAD mouse model of Alzheimer’s disease, the UCSF team deleted Adgrg1 specifically in microglia and observed the consequences. Loss of ADGRG1 impaired activation of the transcription factor MYC and reduced expression of genes tied to cellular homeostasis, phagocytosis, and lysosomal function. Functionally, microglia without ADGRG1 were far less able to phagocytose amyloid-beta, leading to faster plaque growth, increased neuronal degeneration, and measurable learning and memory deficits in mice.
Complementary assays in human embryonic stem cell–derived microglia corroborated the mouse findings by showing that ADGRG1 is required for efficient Aβ uptake. Reanalysis of existing human transcriptomic data further supported the idea that individuals with more ADGRG1 in microglia tended to exhibit milder cognitive impairment and fewer plaques at death, while those with low ADGRG1 showed more severe pathology.
The pathway uncovered connects ADGRG1 signaling to MYC activation, which in turn upregulates genes that equip microglia for sustained homeostatic and lysosomal activity. Because GPCRs are among the most commonly targeted protein families in drug discovery, this molecular axis offers a realistic route to develop treatments that enhance the brain’s innate capacity to clear amyloid and protect neurons.
“ADGRG1 appears to help microglia maintain brain health over many years,” said Xianhua Piao, MD, PhD, a UCSF physician-scientist. “Some people are fortunate to have microglia that manage amyloid well. This discovery suggests we might be able to pharmacologically enable that protective state in more people.”
Funding: This research was supported in part by the National Institutes of Health (P01AG019724, P50AG023501, R01NS094164, R01NS108446, K99AG081694), the Consortium for Frontotemporal Dementia Research, the Tau Consortium, the Alzheimer’s Association (23AARG-NTF-1030341), the Cure Alzheimer’s Fund, and a BrightFocus Foundation postdoctoral fellowship (A2021020F).
About this Alzheimer’s disease and neurology research news
Author: Levi Gadye
Source: UCSF
Contact: Levi Gadye – UCSF
Image: The image is credited to Neuroscience News
Original Research: Open access.
“G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer’s disease through MYC activation” by Xianhua Piao et al., Neuron. DOI: 10.1016/j.neuron.2025.06.020
Abstract
G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer’s disease through MYC activation
Germline genetic studies implicate microglial biology in Alzheimer’s disease susceptibility and outcomes, but the molecular drivers of protective microglial responses are not fully understood. This study examines the role of microglial ADGRG1, an adhesion GPCR selectively expressed in yolk-sac–derived microglia, using the 5xFAD mouse model of AD.
Transcriptomic analyses show that ADGRG1 activates MYC, triggering a program of gene expression that enhances homeostatic maintenance, phagocytic capacity, and lysosomal function—features characteristic of a protective microglial phenotype. Deleting Adgrg1 in microglia impairs MYC activation, increases amyloid-beta deposition, worsens neuronal loss, and produces cognitive deficits. Functional studies in mouse models and human embryonic stem cell–derived microglia confirm that ADGRG1 is necessary for amyloid-beta phagocytosis.
Together, these results reveal a GPCR-mediated pathway that promotes a protective microglial state via MYC activation and suggest therapeutic strategies aimed at enhancing microglial functional competence to slow Alzheimer’s disease progression.