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MS4A4A and MS4A6A: New targets to enhance microglia protective function in Alzheimer's disease
David V Hansen1, Celeste M Karch2, Drishya Mainali3
1Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, USA.
Abstract:
MS4A4A and MS4A6A are microglia-expressed genes linked to Alzheimer's disease risk. In this issue of Neuron, Rosner et al.1 show that these proteins cooperatively restrain TREM2 signaling, dampening protective microglial responses and highlighting MS4A inhibition as a potential strategy to rejuvenate the brain's innate immune system in Alzheimer's disease.
Insights
Researchers found that MS4A4A and MS4A6A proteins restrain protective microglial responses in Alzheimer's disease. Inhibiting these proteins may rejuvenate the brain's immune system for therapeutic benefit.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia, the brain's immune cells, play a critical role in Alzheimer's disease (AD) pathogenesis.
- MS4A4A and MS4A6A are genes expressed in microglia and associated with increased AD risk.
- TREM2 signaling in microglia is crucial for their protective functions in AD.
Purpose of the Study:
- To investigate the functional role of MS4A4A and MS4A6A proteins in microglia.
- To determine the interaction between MS4A4A/MS4A6A and TREM2 signaling pathways.
- To explore the therapeutic potential of targeting MS4A proteins in Alzheimer's disease.
Main Methods:
- Utilized genetic and proteomic approaches in microglial cell models.
- Investigated the impact of MS4A4A and MS4A6A on TREM2 receptor signaling.
- Assessed microglial responses under conditions relevant to Alzheimer's disease pathology.
Main Results:
- MS4A4A and MS4A6A proteins were found to cooperatively inhibit TREM2 signaling.
- This inhibition dampens essential protective microglial functions.
- The findings reveal a novel mechanism by which MS4A proteins influence neuroinflammation in AD.
Conclusions:
- MS4A4A and MS4A6A act as negative regulators of microglial protective responses in Alzheimer's disease.
- Targeting MS4A proteins offers a potential therapeutic strategy to enhance beneficial microglial activity.
- Modulating MS4A function could help rejuvenate the brain's innate immune system to combat AD.
