ABSTRACT: Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are known to increase the risk of developing Alzheimer disease and Parkinson's disease (PD). However, the potential role of TREM2 effect on synucleinopathy has not been characterized. In this study, we investigated whether loss of TREM2 function affects α-synucleinopathy both in vitro and in vivo. In vitro, BV2 microglial cells were exposed to α-synuclein (α-syn) in the presence or absence of TREM2 small interference RNA. For in vivo studies, wild-type controls and TREM2 gene knockout mice were intracranially injected in the substantia nigra with adeno-associated viral vectors expressing human α-syn (AAV-SYN) to induce PD. Our results revealed that knockdown of TREM2 aggravated α-syn-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2-conditioned medium. In mice, TREM2 knockout exacerbated dopaminergic neuron loss in response to AAV-SYN. Moreover, both in vitro and in vivo TREM2 deficiency induced a shift from an anti-inflammatory toward a proinflammatory activation status of microglia. These data suggest that impairing microglial TREM2 signaling aggravates proinflammatory responses to α-syn and exacerbates α-syn-induced neurodegeneration by modulating microglial activation state.-Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., Lou, H. TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models.
