Therapeutics: Sphingomyelin phosphodiesterase 3 (SMPD3; NSMASE2); microtubule-associated protein τ (tau; MAPT; FTDP-17); colony-stimulating factor 1 receptor (C

Mouse studies suggest depleting microglial cells in the brain or inhibiting SMPD3 could help treat AD. In normal mice, intracerebrally injected microglia-derived exosomes loaded with human tau oligomers were taken up by neurons, whereas intracerebrally injected free human tau oligomers were not. In a transgenic mouse model of AD expressing mutant human tau, PLX3397 - an inhibitor of the microglia survival factor CSF1R - decreased numbers of microglia in the brain and the spread of mutant tau from neuron to neuron, and increased synaptic transmission compared with no treatment. Also in the mouse model, knockdown or small molecule inhibition of SMPD3 decreased microglial secretion of exosomes and the inter-neuron transmission of tau compared with normal SMPD3 expression or vehicle, respectively. Next steps include testing whether PLX3397 or inhibition of SMPD3 increases cognitive performance in mouse models of AD. (See "Microglia Strike Again", page 11)...