5,6-Di­oxo-1,10-phenanthrolin-1-ium trifluoro­methane­sulfonate

In the structure of the title salt, C12H7N2O2 +·CF3SO3 −, the cation participates in hydrogen bonding with the dione group of an adjacent cation as well as with the trifluoro­methane­sulfonate anion. In addition, there is an extensive network of C—H⋯O inter­actions between the cations and anions. There are two formula units per asymmetric unit. The crystal studied exhibits inversion twinning

Bis(1,10-phenanthroline-5,6-dione-κ2 N,N′)silver(I) tetra­fluoridoborate

In the structure of the title compound, [Ag(C12H6N2O2)2]BF4 or [AgL 2]BF4 (L = phendione), the Ag and B atoms are located on twofold rotation axes. The dihedral angle between the two phendione ligands is 36.7 (2)°. The coordination about the AgI center is distorted tetra­hedral (τ4 = 0.546). The crystal structure is consolidated by weak C—H⋯O(phendione) and C—H⋯F(BF4 −) inter­actions. The BF4 − counter-anion is strongly disordered and was modelled with two sets of idealized F atoms

Acetato(1,10-phenanthroline-5,6-dione)silver(I) trihydrate

In the structure of the title compound, [Ag(C2H3O2)(C12H6N2O2)]·3H2O, the AgI atom is coordinated by both 1,10-phenanthroline-5,6-dione N atoms and one O atom from the acetate anion. The three water mol­ecules are involved in extensive hydrogen bonding to each other and to the acetate O and 1,10-phenanthroline-5,6-dione O atoms. In addition, there are weak C—H⋯O inter­actions

AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD

Exosomes regulate microglia activation during inflammation and aging

Proper regulation of inflammatory responses is critical for effective microglia function in physiology and disease. While much emphasis is placed on mechanisms driving microglia activation, there remains a gap in knowledge on how microglia resolve or modulate inflammatory activation. Here we provide a comprehensive analysis of exosome regulation of microglia inflammatory response, highlighting a novel anti-inflammatory function of exosomes. First, microglia-derived exosomes contain immune molecules that are sufficient to propagate signals driving transcriptional changes associated with increased inflammatory cytokine production and phagocytic clearance in recipient microglia. Secondly, microglia with impaired exosome biogenesis display altered inflammatory kinetics, characterized by exaggerated and prolonged expression of pro-inflammatory molecules in response to acute and chronic aging-associated inflammation. This robust anti-inflammatory function of exosomes is manifested in part through the release of proinflammatory microRNAs, such miR-155. Taken together, our study identifies exosomes as critical mediators of inflammatory communication in the brain that play important roles in intracellular resolution of microglia inflammation