TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways

Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy

Equilibrium speciation in moderately concentrated formaldehyde−methanol−water solutions investigated using 13C and 1H nuclear magnetic resonance spectroscopy

We used 13C and 1H NMR spectroscopy to examine the equilibrium speciation in formaldehyde−methanol−water solutions at moderate formaldehyde concentrations such as those used in the synthesis of formaldehyde-based organic gels. Concentrations of small methylene glycol oligomers and their methoxylated forms found in these solutions were quantitatively determined over a range of formaldehyde concentrations and methanol−water ratios, and at temperatures between 10 and 55 °C. Using the measured concentrations, equilibrium constants for methylene glycol dimer and trimer formation as well as methoxylation of these oligomers were calculated. Based on this, we developed a quantitative equilibrium model for calculation of formaldehyde-related species concentrations over a range compositions relevant for formaldehyde based sol−gel processes allowing for more rational design of formaldehyde polymerization systems