نبذة مختصرة : Triggering Receptor Expressed on Myeloid cells-2 (TREM2) is an immunoreceptor with genetic links to human neurodegenerative disorders. TREM2 is thought to alter the microglial response to neurodegeneration in a protective way. This dissertation describes the generation of two separate lines of Bacterial Artificial Chromosome (BAC) transgenic animals, BAC-TREM2 and BAC-TREM2-R47H mice, useful in better understanding the role of TREM2 in vivo. BAC-TREM2 is designed to express human TREM2, increase TREM2 gene dosage, and enhance TREM2 signaling, creating mice with efficient microglia primed to handle a damaged and degenerating brain. BAC-TREM2-R47H is designed to express the Alzheimer’s disease-associated R47H allele in order to determine if R47H TREM2 has lost TREM2’s protective functions or gains new toxic functions. We find that BAC-TREM2 mice correctly express human TREM2. In addition, cultured microglia demonstrate increased Ca2+ signaling when stimulated with the TREM2 ligand phosphatidylserine and have suppressed pro-inflammatory cytokine secretion when stimulated with lipopolysaccharide, both signs of increased TREM2 signaling. To test the effect of increased TREM2 gene dosage in vivo, we crossed BAC-TREM2 mice with two mouse amyloidosis models of Alzheimer’s disease, APPswe/PS1ΔE9 and 5xFAD mice. We found BAC-TREM2 significantly reduced microgliosis around amyloid-beta plaques in both models without reducing astrogliosis. This changed in microglia activation was accompanied by a significant improvement in a contextual fear conditioning learning task that is disrupted in APP/PS1 mice, but no change in hyperactivity found in these mice. Altogether, this study suggests BAC-TREM and BAC-TREM2-R47H will useful tools for the study of TREM2 function in vivo, and that TREM2 signaling is a promising target for manipulating microglia in order to improve the innate immune response to neurodegeneration.
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