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The Alzheimer's disease risk genes MS4A4A and MS4A6A cooperate to negatively regulate TREM2 and microglia states
Dalya Rosner1, Jiahong Sun1, Rita Cacace2
1Alector, Inc., South San Francisco, CA 94080, USA.
Abstract:
Genetic variations in MS4A4A and MS4A6A Triggering receptor expressed on myeloid cells 2 (TREM2) are linked to the regulation of cerebrospinal-fluid-soluble TREM2 levels and are associated with Alzheimer's disease (AD) risk and progression. By modulating MS4A4A using knockout, overexpression, and degrading antibodies in macrophages, microglia, non-human primates (NHPs), and a mouse model of amyloid pathology, we provide evidence that MS4A4A and MS4A6A are negative regulators of both the transmembrane and soluble TREM2 proteins. Additionally, MS4A4A limits microglia viability, phagocytosis, and lysosomal function, processes that contribute to disease pathology. Mechanistically, we find that MS4A4A restrains TREM2 by an indirect mechanism: MS4A4A interacts with MS4A6A and protects it from degradation. MS4A6A, in turn, forms a complex with and blocks the co-receptor DNAX-activating protein of 12 kDa (DAP12), which modulates the levels of TREM2 and other receptors. Taken together, the data indicate that MS4A4A and MS4A6A are cooperative post-transcriptional negative regulators of TREM2 and microglial function as well as potential drug targets for AD.
Insights
MS4A4A and MS4A6A proteins negatively regulate Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and microglial function, impacting Alzheimer's disease (AD) pathology and offering potential therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Genetic variations in MS4A4A and MS4A6A are associated with Alzheimer's disease (AD) risk.
- Triggering Receptor Expressed on Myeloid cells 2 (TREM2) plays a crucial role in microglial function and AD pathogenesis.
- Soluble TREM2 levels in cerebrospinal fluid are linked to AD progression.
Purpose of the Study:
- To investigate the regulatory roles of MS4A4A and MS4A6A in TREM2 expression and microglial function.
- To elucidate the molecular mechanisms by which MS4A4A and MS4A6A influence TREM2 levels and microglial activity.
- To assess the therapeutic potential of targeting MS4A4A and MS4A6A for Alzheimer's disease.
Main Methods:
- Modulation of MS4A4A expression (knockout, overexpression, antibody-mediated degradation) in cell cultures (macrophages, microglia) and in vivo models (non-human primates, amyloid mouse model).
- Assessment of TREM2 protein levels (transmembrane and soluble forms).
- Evaluation of microglial functions including viability, phagocytosis, and lysosomal activity.
- Mechanistic studies involving protein-protein interactions and complex formation (MS4A4A, MS4A6A, DAP12).
Main Results:
- MS4A4A and MS4A6A act as negative regulators of both transmembrane and soluble TREM2.
- MS4A4A negatively impacts microglial viability, phagocytosis, and lysosomal function.
- MS4A4A stabilizes MS4A6A by preventing its degradation, and MS4A6A complexes with and inhibits the co-receptor DAP12.
- These interactions indirectly modulate TREM2 levels and downstream signaling.
Conclusions:
- MS4A4A and MS4A6A are cooperative post-transcriptional negative regulators of TREM2 and microglial function.
- Dysregulation of MS4A4A and MS4A6A contributes to Alzheimer's disease pathology.
- MS4A4A and MS4A6A represent potential therapeutic targets for Alzheimer's disease treatment.
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