TREM2 deficiency aggravates neuroinflammatory response and cognitive impairment via disease-associated microglia in Parkinson's disease models

Abstract

This study explores whether Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) regulates the distinct disease-related microglia (DAM) phenotype and exerts a protective role in cognitive impairment in Parkinson's disease (PD). Adeno-associated virus carrying TREM2 shRNA (AAV-TREM2-shRNA) was injected into the bilateral hippocampus of the A53T α-Synuclein (α-Syn) transgenic PD mouse model; Additionally, lentivirus was transduced into BV2 microglial cells to knock out the expression of TREM2, which were subsequently stimulated with α-Syn preformed fibrils (PFF). Furthermore, cognitive status of mice, α-Syn aggregation, microglia status, expression of inflammatory factors, pro-inflammatory and anti-inflammatory DAM markers, MAPK and NF- κB pathway activation status and neuron apoptosis were evaluated. TREM2 deficiency induced cognitive impairment in A53T α-Syn PD mice by decreased performance in the novel objective recognition and Morris water maze tests. TREM2 knockdown resulted in synaptic loss, microglial activation, increased inflammatory factors, and MAPK and NF- κB pathway activation in the hippocampus of mice. In vitro, TREM2 deficiency exacerbated the inflammatory response of BV2 cells stimulated by α-Syn PFF by inhibiting anti-inflammatory DAM, and promoting neuronal apoptosis and Ser129-phosphorylation of α-Syn. TREM2 knockdown also promoted pro-inflammatory DAM activation and increased inflammatory factors expression via the ERK1/2 signaling pathway. Our findings suggest that TREM2 plays a protective role in cognitive impairment and promotes anti-inflammatory DAM activation via the ERK1/2 signaling pathway in PD mice, providing novel insight into the immunopathogenesis of cognitive impairments in PD.