Date of Award
Doctor of Philosophy (PhD)
Carriers of the R47H allele of the microglia-specific lipid receptor TREM2 have a greatly increased risk of developing Alzheimerճ disease. The objective of this dissertation is to develop further mechanistic knowledge about how TREM2 is regulated and how TREM2 mutations affect microglia and neurodegeneration. Using an in vitro reporter assay, we find that several AD risk-associated TREM2 mutations decrease ligand-dependent activation. Using humanized TREM2 mice, we find that in vivo, the R47H mutation leads to reduced microglia activation and response to A_, as well as decreased shedding of soluble TREM2. These results suggest that TREM2 is protective during disease. We find that TREM2-deficient macrophages in vitro are more susceptible to stress-induced loss of mTOR signaling, increased autophagy, and low-energy status. In vivo, microglia similarly fail to maintain mTOR signaling and increase autophagy in an A_ mouse model, which could be rescued by enhancing energy utilization with long-term cyclocreatine supplementation. These results suggest that TREM2 is playing a fundamental role in maintaining microglia health and survival rather than triggering a specific activation signature. Finally, we perform an unbiased CRISPR-Cas9 knockout screen to identify and characterize pathways that regulate TREM2 surface expression, identifying TMEM131 as a suppressor of TREM2 surface expression. We further demonstrate that TMEM131 regulation of TREM2 does not involve cleavage or degradation of TREM2 from the cell surface or require the unique intramembranous charge of TREM2. These results provide a stepping stone for identifying novel therapeutic targets related to TREM2.
Chair and Committee
John Cirrito, Brian Edelson, Gwendalyn Randolph, Gregory Wu,
Song, Wilbur Madison, "Regulation and Function of TREM2-dependent Pathways in Neurodegeneration" (2020). Arts & Sciences Electronic Theses and Dissertations. 2244.