Scientists discover the receptor that helps your brain clean itself—and fight Alzheimer’s

Good news!

"Scientists at UCSF have uncovered how certain immune cells in the brain, called microglia, can effectively digest toxic amyloid beta plaques that cause Alzheimer’s. They identified a key receptor, ADGRG1, that enables this protective action. When microglia lack this receptor, plaque builds up quickly, causing memory loss and brain damage. But when the receptor is present, it seems to help keep Alzheimer's symptoms mild. Since ADGRG1 belongs to a drug-friendly family of receptors, this opens the door to future therapies that could enhance brain immunity and protect against Alzheimer’s in more people."

From the highlights and summary:

"Highlights

• ADGRG1 activates MYC to induce a protective microglial state in Alzheimer’s disease

• MYC activation upregulates genes involved in phagocytosis and lysosomal activity

• Loss of microglial ADGRG1 impairs Aβ clearance and exacerbates AD pathology

Summary

Germline genetic architecture of Alzheimer’s disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model.

Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions, thereby promoting a protective microglial state. We demonstrate that deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, exacerbated neuronal loss, and cognitive deficits.

Functional assays in mouse models and human embryonic stem cell-derived microglia confirm that ADGRG1 is required for Aβ phagocytosis. These findings uncover a GPCR-mediated pathway that drives a protective microglial state via MYC activation, suggesting potential therapeutic strategies to alleviate AD progression by enhancing microglial functional competence."

Scientists discover the receptor that helps your brain clean itself—and fight Alzheimer’s | ScienceDaily

G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation (no public access)

Graphical abstract