Editors' ChoiceFRONTOTEMPORAL DEMENTIA

Immunity at the forefront of the brain: A new genetic model of FTD

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Science Translational Medicine  14 Jun 2017:
Vol. 9, Issue 394, eaan5227
DOI: 10.1126/scitranslmed.aan5227

Abstract

Functional characterization of a genetic variant linked to frontotemporal dementia in a murine model reveals deficits in cerebral immune response and metabolism.

Frontotemporal dementia (FTD) is a group of neurodegenerative disorders caused by cell loss in the brain’s frontal and/or temporal lobes. Clinically, FTD is characterized by behavioral impairments, language difficulty, and progressive memory loss. The etiology of FTD is not well understood, but a handful of variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been shown to be associated with FTD. TREM2 is an innate immune receptor that regulates intramembrane proteolysis and is expressed in all myeloid cells. In the brain, TREM2 is almost exclusively expressed by microglia, the immunocompetent cell population of the central nervous system, and is implicated in lipoprotein binding, phagocytosis, protein clearance, and inflammation. Here, Kleinberger et al. used CRISPR/Cas9 genome editing to generate a mouse model of FTD-like syndrome. The animals express a rare TREM2 mutation observed in FTD: substitution of methionine for threonine at position 66 (TREM2 p.T66M). This strain improves upon existing models and allows in vivo functional assessments of a clinically relevant mutation involved in FTD.

TREM2 p.T66M mice exhibited a gene dose-dependent decrease in soluble TREM2, a cleavage product involved in microglial activation. Macrophage cell lines generated from homozygous TREM2 p.T66M mice revealed decreased proliferation and cell survival compared with wild-type mice, with less consistent decreases also observed in heterozygous animals. Homozygous mice also had a higher cytokine response to lipopolysaccharide injection, suggesting increased response to inflammation. Longitudinal brain imaging to assess cerebral microglial activation indicated an age-related functional deficit that was accompanied by decreased microglial immunoreactivity. Cerebral perfusion and cerebral glucose metabolism were assessed at single time points (6 and 12 months, respectively) and were also decreased in homozygous TREM2 p.T66M mice. A correlation between measures of microglial activation and glucose metabolism was observed at the latter time point, which suggests a potential role for the brain’s immune response in the regulation of brain energy metabolism.

Taken together, this study shows that a mutation linked to FTD affects microglial function, cerebral blood flow, and cerebral glucose metabolism in vivo. This model will set the stage for future work that investigates therapeutic approaches for restoring TREM2 function.

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