TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

Cheryl E. G. Leyns, Jason D. Ulrich, Mary B. Finn, Floy R. Stewart, Lauren J. Koscal, Javier Remolina Serrano, Grace O. Robinson, Elise Anderson, Marco Colonna, and David M. Holtzman,: Proceedings of the National Academy of Sciences of the United States of America, Volume 114, Issue 43, 24 October 2017, Pages 11524-11529 Read More

Abstract

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer’s disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found TREM2 is protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglial signaling and are deleterious. However, the potential role of TREM2 in the context of tau pathology has not yet been characterized. In this study, we crossed Trem2+/+ (T2+/+) and Trem2-/- (T2-/-) mice to the PS19 human tau transgenic line (PS) to investigate whether loss of TREM2 function affected tau pathology, the microglial response to tau pathology, or neurodegeneration. Strikingly, by 9 mo of age, T2-/-PS mice exhibited significantly less brain atrophy as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared with T2+/+PS mice. However, no TREM2- dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2-/-PS mice exhibited significantly reduced microgliosis in the hippocampus and piriform cortex comparedwith T2+/+PS mice. Gene expression analyses and immunostaining revealed microglial activation was significantly attenuated in T2-/- PS mice, and there were lower levels of inflammatory cytokines and astrogliosis. These unexpected findings suggest that impairing microglial TREM2 signaling reduces neuroinflammation and is protective against neurodegeneration in the setting of pure tauopathy.
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Posted on November 11, 2017
Posted in: Clocks & Sleep, HPAN, Neurodegeneration, Publications Authors: ,