Membrane-spanning 4-domains subfamily A member 4A and Membrane-spanning 4-domains subfamily A member 6A (MS4A4A/MS4A6A)

Membrane-spanning 4-domains subfamily A member 4A (MS4A4A) and Membrane-spanning 4-domains subfamily A member 6A (MS4A6A) are members of the MS4A family of four-transmembrane proteins, primarily expressed in myeloid cells such as microglia and macrophages [1, 9]. They have emerged as significant genetic risk factors for Alzheimer's disease (AD), with variants in the MS4A gene cluster strongly associated with soluble TREM2 (sTREM2) levels in cerebrospinal fluid [1, 30]. Mechanistically, MS4A4A interacts with and stabilizes MS4A6A, which in turn forms an inhibitory complex with DAP12, the essential co-receptor for TREM2 [1, 2]. This interaction prevents DAP12 from stabilizing TREM2 on the cell surface, thereby acting as a negative regulator of TREM2-mediated neuroprotective functions, including phagocytosis, survival, and lipid metabolism [1, 26]. In oncology, MS4A4A is linked to M2 macrophage polarization and tumor progression in glioblastoma [14]. Therapeutic development, such as Alector's AL044, focuses on modulating this axis—potentially through MS4A4A degradation—to boost TREM2 signaling and enhance microglial clearance of amyloid-beta in AD [1, 22]. Additionally, MS4A6A has been implicated in other neurodegenerative processes and as a prognostic marker in various malignant tumors [8, 9]. The target complex represents a novel immune checkpoint in the brain, where its inhibition aims to rejuvenate microglial activity against disease pathology [1, 22].

Other names

CD20-like 1CD20L14SPAN1MS4A4CD20-like 3CD20L34SPAN3MS4A6

Modulation of MS4A4A/MS4A6A levels (e.g., via degradation) to regulate TREM2 stabilization and signaling through the DAP12 co-receptor.