Mechanism of TREM2/DAP12 complex affecting β-amyloid plaque deposition in Alzheimer's disease modeled mice through mediating inflammatory response

Abstract

To investigate the mechanism of TREM2/DAP12 complex in mediating inflammatory responses that affect β-amyloid plaque deposition in Alzheimer's disease (AD) modeled mice. We measured escape latency and platform crossing time using the Morris water maze image automatic acquisition and software analysis system in TREM2 and DAP12 microglia knockout AD model mouse. We monitored the deposition of Aβ plaques in the mouse hippocampus using Congo red staining and measured levels. of inflammatory factors IL-6 and TNF-α by ELISA. Newborn mice with TREM2 knockout were selected for primary microglia isolation and culture, and Aged oligomer Aβ1-42 was added to the microglial culture medium to simulate the AD environment in vivo. Co-immunoprecipitation assay was used to detect the interaction between DAP12 and TREM2, and measured the inflammatory response induced by lipopolysaccharide (LPS) in mice with TREM2 and DAP12 knockdown through adeno-associated virus in BV2 microglia. The escape latency of the AD model mice with TREM2 and DAP12 knockout was higher and the number of crossing platforms lower than in the control group, whereas Aβ deposition and levels of inflammatory factors were higher. In TREM2 knockout microglial cultured with Aβ1-42, levels of IL-6 and TNF-α increased. Immunoprecipation pull-down assays showed that TREM2 binds to the membrane receptor DAP12 to form a complex. Knockout of TREM2 or DAP12 can inhibit LPS-induced microglial inflammatory responses. The TREM2/DAP12 complex inhibits the microglial inflammatory response through the JNK signaling pathway, thereby reducing the deposition of Aβ plaques and attenuation the behavioral manifestation in a mouse AD model.