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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2016)

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.

    Cover page: Novel Mice for Investigating Triggering Receptor Expressed on Myeloid Cells-2 (TREM2), an Alzheimer’s Disease-Linked Immune Gene That Alters Microglia Responses to Neurodegeneration
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2018)
    Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models.
      Cover page: Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models.
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