Project Summary: Alzheimer’s disease (AD) is a progressive dementia effecting 1 in 8 Americans over the age of 65. Currently no cure or effective treatment is available for AD. Recently, the field has recognized the role of microglia in the pathogenesis and progression of AD. Triggering receptor expressed on myeloid cells 2 (Trem2) is a major microglial receptor that when lost results in an aberrant microglial response to amyloid β (Aβ) plaques. We have demonstrated that in the absence of Trem2 microglia fail to cluster around plaques resulting in the plaques being more neurotoxic. We have also found that the primary function of Trem2 in microglia is to boost and sustain microglial metabolism in the setting of chronic stimulation such as the response to Aβ plaques. Finally, we have preliminary evidence that suggests that in response to Aβ plaques microglia become more dependent upon glucose metabolism and less dependent on uptake of locally produced fructose. In contrast Trem2-deficient microglia do not undergo this transition. In this proposal we will further explore the role of microglial sugar metabolism and develop new resources that will be necessary to pursue future research.