Variants in the MS4A gene cluster influence AD risk, at least in part, by tweaking levels of another AD risk factor, TREM2. In a study published in Science Translational Medicine on August 14, researchers co-led by Bruno Benitez, Celeste Karch, Laura Piccio, and Carlos Cruchaga at Washington University in St. Louis tied variants near genes in the membrane-spanning 4-domains subfamily A (MS4A) cluster to concentrations of a shed TREM2 fragment in the cerebrospinal fluid (CSF). They reported that a protective MS4A variant, which promotes expression of two genes in the cluster, appeared to boost shedding of the soluble extracellular domain of the microglial receptor. Another, which raises AD risk and stifles expression of the MS4A4A gene, had the opposite effect.
- MS4A variant associates with higher CSF sTREM2, lowers AD risk.
- Another variant lowers CSF sTREM2, and raises AD risk.
- MS4A4A and TREM2 interact in plasma membrane; MS4A4A overexpression boosts sTREM2 release.
Alzforum covered the bulk of the findings last year, when they were posted on the BioRχiv preprint server (see Jul 2018 news). The STM paper reports some additional data. Using cultured human macrophages as a proxy for microglia, the researchers found that TREM2 and MS4A4A team up within lipid rafts in the plasma membrane. Overexpressing the latter boosted shedding of soluble TREM2; silencing MS4A4A had the opposite effect. They proposed that MS4A4A enhances sTREM2 shedding either by altering its intracellular trafficking, or by somehow modifying its cleavage or release from the cell surface.
The findings cast the membrane-spanning 4-domains subfamily, particularly MS4A4A, as key modulators of sTREM2 release, and provide a putative biological connection between the MS4A gene family, TREM2, and AD risk, the authors wrote. In addition, they suggest that a role for TREM2 in AD pathogenesis is not limited to carriers of AD risk variants in that gene.—Jessica Shugart
- Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, Li Z, Del-Aguila JL, Dube U, Farias FG, Bradley J, Budde J, Ibanez L, Fernandez MV, Blennow K, Zetterberg H, Heslegrave A, Johansson PM, Svensson J, Nellgård B, Lleo A, Alcolea D, Clarimon J, Rami L, Molinuevo JL, Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Ewers M, Harari O, Haass C, Brett TJ, Benitez BA, Karch CM, Piccio L, Cruchaga C. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk. Sci Transl Med. 2019 Aug 14;11(505) PubMed.