Alzheimer’s disease (AD) is one of the most common causes of dementia in older adults, marked by memory loss and cognitive decline. Despite that microglia are known to surround toxic amyloid-beta plaques and exhibit a protective role, the exact mechanism by which microglia shift to a protective state has been unclear. A recent study in Neuron from researchers at the BARI, led by Xian Piao and team sheds light on this issue by focusing on ADGRG1, a receptor found almost exclusively on microglia derived from early embryonic cells. Using a mouse model of AD, the team shows how ADGRG1 drives microglia to adopt a state that boosts their ability to clean up amyloid-beta, protect neurons, and maintain brain function. This discovery is exciting because it reveals a specific pathway that could inspire new treatments to enhance microglia’s beneficial roles without amplifying their harmful ones.
Microglia rely on ADGRG1 to promote amyloid-beta clearance in vivo
Piao and team used the 5xFAD mouse model, which mimics AD by rapidly developing amyloid plaques and cognitive symptoms similar to human patients. Within the 5xFAD background, they created mice in which the Adgrg1 gene was specifically removed from microglia. This approach allowed them to isolate ADGRG1’s role in the adult brain as it responds to AD-like changes. They found that ADGRG1 loss resulted in reduced expression of genes that normally respond to toxic aggregates in AD brains such as phagocytosis, lysosomal function, and lipid metabolic genes. And in both mice and humans, microglia without ADGRG1 had an impaired phagocytosis ability relative to microglia with a normal amount of ADGRG1. In vivo, the researchers found that loss of ADGRG1 led to increased amyloid-beta deposits in the cortex and hippocampal regions of the brain, and that fewer microglia were recruited to these plaques. Further, the mutant mice had an accelerated loss of memory than is typically observed in this mouse model of AD.
The MYC transcription factor – a downstream effector of ADGRG1 microglia signaling
To investigate the transcription factors that might drive the protective microglial state, the Piao lab used a chromatin immunoprecipitation database of the differentially expressed genes in ADGRG1-deficient microglia and identified MYC. Further, MYC was in its more activated state in wild-type microglia expressing ADGRG1, where it was mainly found near amyloid-beta aggregates. Interestingly, inhibition of MYC in vitro and in vivo resulted in more amyloid-beta plaques. Although this transcription factor is extensively studied in the cancer field, its role in brain immune cells is far less characterized. The Piao lab discovery of a MYC role in microglial
phagocytosis highlights the need to study whether MYC may have a broader role in microglial function or neurodegenerative disease.
What’s next for the Piao lab?
The Piao lab is continuing to actively investigate the role of microglial ADGRG1 in tauopathies, with the goal of identifying targets along this pathway for potential translational therapies.