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RSS FeedsTREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer`s disease variant Trem2R47H on murine myeloid cell function [Neurobiology] (Journal of Biological Chemistry)

 
 

17 august 2018 06:00:15

 
TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer`s disease variant Trem2R47H on murine myeloid cell function [Neurobiology] (Journal of Biological Chemistry)
 


Triggering receptor expressed on myeloid cells 2 (TREM2) is an orphan immune receptor expressed on cells of myeloid lineage such as macrophages and microglia. The rare variant R47H TREM2 is associated with an increased risk for Alzheimer`s disease, supporting the hypothesis that TREM2 loss of function may exacerbate disease progression. However, a complete knockout of the TREM2 gene in different genetic models of neurodegenerative diseases has been reported to result in both protective and deleterious effects on disease-related end points and myeloid cell function. Here, we describe a Trem2R47H transgenic mouse model and report that even in the absence of additional genetic perturbations, this variant clearly confers a loss of function on myeloid cells. The Trem2R47H variant-containing myeloid cells exhibited subtle defects in survival and migration and displayed an unexpected dysregulation of cytokine responses in a lipopolysaccharide challenge environment. These subtle phenotypic defects with a gradation in severity across genotypes were confirmed in whole-genome RNA-Seq analyses of WT, Trem2-/-, and Trem2R47H myeloid cells under challenge conditions. Of note, TREM2-activating antibodies that boost proximal signaling abrogated survival defects conferred by the variant and also modulated migration and cytokine responses in an antibody-, ligand-, and challenge-dependent manner. In some instances, these antibodies also boosted WT myeloid cell function. Our studies provide a first glimpse into the boost in myeloid cell function that can be achieved by pharmacological modulation of TREM2 activity that can potentially be ameliorative in neurodegenerative diseases such as Alzheimer`s disease.


 
119 viewsCategory: Biochemistry
 
Preconditioning c-Kit-positive human cardiac stem cells with a nitric oxide donor enhances cell survival through activation of survival signaling pathways. [Additions and Corrections] (Journal of Biological Chemistry)
Molecular basis for the loss-of-function effects of the Alzheimer`s disease-associated R47H variant of the immune receptor TREM2 [Neurobiology] (Journal of Biological Chemistry)
 
 
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