TREM2 haploinsufficiency impairs microglia’s response to injury and exacerbates tau pathology in a tauopathy mouse model [RNA-Seq]

Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. The link between mutations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a microglia-expressed gene, and the increased risk for developing late-onset AD suggests a detrimental role for microglia in disease pathophyioslogy. Hemizygous TREM2 mutations are posited to increase risk for AD through loss-of-function haploinsufficiency. The effects of TREM2 haploinsufficiency on tau pathology and tau-associated deficits have not yet been characterized. Using in vivo imaging, we showed that TREM2 haploinsufficiency, but not complete loss of TREM2, resulted in a striking agedependent impairment in microglia’s response to injury without affecting baseline motility. This TREM2-dependent effect on microglial motility is consistent with transcriptomic alterations in cell motility uncovered with unbiased RNAsequencing analysis. Moreover, TREM2 haploinsufficiency, but not complete loss of TREM2, exacerbated phosphorylated tau pathology in transgenic mice expressing mutant human tau. In addition, TREM2 haploinsufficiency increased tau inclusions and tau-mediated inflammation without further exacerbating neuronal loss. Our findings demonstrate for the first time that TREM2 haploinsufficiency induces deficits in a tauopathy mouse model, supporting the notion that the hemizygous missense variant results in loss-of-function. Adult microglia were isolated from 3-5 month old TREM2+/+, TREM2+/- and TREM2-/- mice using CD11b magnetic beads, followed by total RNA isolation using an RNeasy kit (Qiagen).