The Alzheimer’s disease risk genes MS4A4A And MS4A6A cooperate to negatively regulate TREM2 and modify Microglia States.

Genetic variations in MS4A4A and MS4A6A are linked to the regulation of cerebrospinal fluid soluble TREM2 levels and are associated with Alzheimer's disease risk and progression. By modulating MS4A4A using CRISPR knockout and degrading antibodies in macrophages, microglia, non-human primates and a humanized mouse models of amyloid pathology, we provide evidence that MS4A4A and MS4A6A are negative regulators of both the transmembrane and soluble TREM2 proteins. Additionally, they limit microglia viability, phagocytosis and lysosomal function, processes which 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 DAP12, which is required for the stability, cell surface localization and signaling of TREM2 and other receptors. Taken together, the data indicates that MS4A4A and MS4A6A are cooperative post-transcriptional negative regulators of TREM2 and microglial function and potential drug targets for AD.