UCSF researchers have pinpointed a crucial brain receptor that helps immune cells called microglia clear out toxic amyloid beta plaques linked to Alzheimer’s disease.
When microglia have plenty of this receptor, they efficiently “eat” the plaques, keeping symptoms mild. But without it, plaques accumulate quickly, leading to severe memory loss and brain damage.
Microglia’s Surprising Role in Alzheimer’s Defense
In Alzheimer’s disease, certain proteins such as amyloid beta can clump together into structures called plaques, which harm brain cells.
In some individuals, however, the brain’s immune cells, known as microglia, are able to clear away much of this buildup before it causes significant damage. This results in fewer plaques, smaller in size, and noticeably milder symptoms.
Discovery of the ADGRG1 Receptor
A team at the University of California, San Francisco has pinpointed a molecular receptor that enables microglia to consume and break down amyloid beta plaques efficiently.
When this receptor, called ADGRG1, was absent, the microglia removed very little of the harmful protein. In a mouse model of Alzheimer’s, the loss of ADGRG1 led to a rapid increase in plaque formation, degeneration of brain tissue, and declines in learning and memory abilities.
“We think this receptor helps microglia do their job of keeping the brain healthy over many years,” said Xianhua Piao, MD, PhD, a physician-scientist in the UCSF Department of Pediatrics.
Gene Expression Clues in Human Brains
Indeed, when the researchers reanalyzed a prior study of gene expression in the human brain, they found that individuals who died of mild Alzheimer’s had microglia with abundant ADGRG1, 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 little ADGRG1, and the plaques proliferated.
ADGRG1 is one of hundreds of G protein-coupled receptors, which are routinely targeted in drug development. This bodes well for a rapid translation of the discovery into new therapies.
Boosting Everyone’s Brain Defenders
“Some people are lucky to have responsible microglia,” Piao said. “But this discovery creates an opportunity to develop drugs to make microglia effective against amyloid-beta in everyone.”
Reference: “G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer’s disease through MYC activation” by Beika Zhu, Andi Wangzhou, Diankun Yu, Tao Li, Rachael Schmidt, Stacy L. De Florencio, Lauren Chao, Alicia L. Thurber, Minqi Zhou, Zeina Msheik, Yonatan Perez, Lea T. Grinberg, Salvatore Spina, Richard M. Ransohoff, Arnold R. Kriegstein, William W. Seeley, Tomasz Nowakowski and Xianhua Piao, 25 July 2025, Neuron.
DOI: 10.1016/j.neuron.2025.06.020
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6 Comments
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If you don’t tell us where to acquire this… what is the point.
This is nonsense. The only people that still think amyloid causes Alzheimer’s Disease are patent holders that don’t want to see their patents invalidated and investors that don’t want to see their investments in the companies that hold those patents depreciate. Google ARIA if you have trouble accepting that.
Can having more efficient microglia lead to better outcomes even if the amyloid hypothesis is a crock of sh*t? Absolutely. Alzheimer’s disease is triggered by an overactive Complement System, overactive because the CSF and ISF are littered with cellular and microbial debris. If upregulating ADGRG1 helps improve microglial function that’s great. Get right to it. But don’t bulls*** desperate people with the Amyloid Hypothesis. That old thinking was never supported by the science.
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