biostudies-literatureFremuth LENational Institute of Neurological Disorders and StrokeAssisi Foundation of Memphis IncAmerican Lebanese Syrian Associated CharitiesNINDS NIH HHSNCI NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS115204https://www.ebi.ac.uk/biostudies/studies/S-EPMC11874873biostudies-literatureUnknown44(1)Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here, we examine how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimateCell reportsNeuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.PMC11874873R01 GM104981P30 CA021765RF1 NS123174Fremuth LEAnnunziata IHu HWeesner JAvan de Vlekkert DAlessandra d'AzzofalseNeuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here, we examine how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimate2025-01-01T00:00:00Z2025 Jan2026-06-01T10:39:51.413Z2025-04-05T11:18:23.603ZS-EPMC118748733981790910.1016/j.celrep.2024.115204