ADGRG1 in Microglia Facilitates Clearance of Amyloid in the Aging Brain
Specific receptors on the surface of immune cells enable these cells to ingest and clear specific forms of metabolic waste. Receptors are proteins that are produced via the usual mechanisms of gene expression. The amount produced can change with age and circumstances, as epigenetic regulation of gene expression changes, and this will affect the ability of immune cells to act against specific targets. Researchers here report on the ability of the innate immune cells known as microglia to clear excess amyloid-β from the brain, and show that it is dependent on expression of the ADGRG1 receptor. In severe Alzheimer's disease, microglia lack sufficient ADGRG1 to effectively clear plaque. Whether this is a contributing cause of Alzheimer's disease rather than a side-effect remains to be demonstrated conclusively, but this is far from the only data suggesting that microglial dysfunction is important in neurodegenerative conditions.
In Alzheimer's disease, proteins like amyloid beta form clumps, known as plaques, that damage the brain. But in some people, immune cells called microglia break down these proteins before they can cause harm. This leads to fewer and smaller clumps - and much milder symptoms. Researchers identified a protein called ADGRG1 that enables microglia to gobble up and digest plaques. When the researchers removed this protein, which is a kind of receptor, from mice, their microglia barely nibbled on the plaques. This led to the rapid buildup of plaques, neurodegeneration and problems with learning and memory.
When the researchers reanalyzed a prior study of gene expression in the human brain, they found that individuals who died while exhibiting mild Alzheimer's had microglia with lots of these receptors, and mild cognitive impairment - implying that the microglia ate well and kept the disease in check. But in those who died of severe Alzheimer's, the microglia had very few of the receptors, and the plaques proliferated. ADGRG1 is part of a large family of receptors, called G protein-coupled receptors, that are routinely targeted in drug development. This bodes well for a rapid translation of the discovery into new therapies.
Link: https://www.ucsf.edu/news/2025/07/430411/immune-cells-eat-molecular-trash-to-keep-alzheimers-bay