Acute <i>Trem2</i> reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice.

Abstract

Heterozygous genetic variants within the <i>TREM2</i> gene show a strong association with increased Alzheimer's disease (AD) risk. Amyloid beta-depositing mouse models haploinsufficient or null for <i>Trem2</i> have identified important relationships among TREM2, microglia, and AD pathology; however, results are challenging to interpret in the context of varying microglial phenotypes and disease progression. We hypothesized that acute <i>Trem2</i> reduction may alter amyloid pathology and microglial responses independent of genetic <i>Trem2</i> deletion in mouse models. We developed antisense oligonucleotides (ASOs) that potently but transiently lower <i>Trem2</i> messenger RNA throughout the brain and administered them to APP/PS1 mice at varying stages of plaque pathology. Late-stage ASO-mediated <i>Trem2</i> knockdown significantly reduced plaque deposition and attenuated microglial association around plaque deposits when evaluated 1 mo after ASO injection. Changes in microglial gene signatures 1 wk after ASO administration and phagocytosis measured in ASO-treated cells together indicate that microglia may be activated with short-term <i>Trem2</i> reduction. These results suggest a time- and/or dose-dependent role for TREM2 in mediating plaque deposition and microglial responses in which loss of TREM2 function may be beneficial for microglial activation and plaque removal in an acute context.