GSE175504
Stimulating microglial glucose metabolism and phagocytosis for post-stroke remyelination and cognitive function recovery
New research shows that disease-associated microglia (DAM) in neurodegenerative brains present features of elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The underlying mechanisms remain poorly understood. Intracellular pHi is important for regulating aerobic glycolysis in microglia, where Na/H exchanger (NHE1) is a key pH regulator by extruding H+ in exchange of Na+ influx. We report here that post-stroke Cx3cr1-CreER+/-;Nhe1flox/flox (Nhe1 cKO) brains displayed stimulation of microglial transcriptomes of rate-limiting enzyme genes for glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation (OXPHOS). The other upregulated genes included the DAM hallmark genes (Apoe, Trem2, Spp1) as well as genes for phagocytosis and LXR/RXR pathway activation. The cKO microglia exhibited increased OXPHOS capacity and higher phagocytic activity, which led to enhanced synaptic pruning, oligodendrogenesis, and remyelination. This study reveals that genetic blockade of microglial NHE1 stimulated glucose immunometabolism to support phagocytosis function for tissue remodeling and post-stroke cognitive function recovery. Overall design: Examination of effect of deletion of Nhe1 in microglia on post-stroke recovery