Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer's disease models.
Fassler Michael,Rappaport Maya Saban,Cuño Clara Benaim,George Jacob
Journal of neuroinflammation
BACKGROUND:Genetic variants and mutations in triggering receptor expressed in myeloid cells (TREM2) are associated with premature and late onset Alzheimer's disease (AD). METHODS:We developed a panel of monoclonal antibodies, the selected lead of which was avidly shown to bind the extracellular domain of human and murine TREM2. RESULTS:By engaging membrane-bound TREM2, the selected antibody was shown to promote their cellular proliferation, uptake of oligomeric beta amyloid/apoptotic neurons, and activation in a Syk and Akt dependent manner. The antibody was shown to avidly bind soluble TREM2 in the CSF from AD patients and blunted the proinflammatory program driven by its intracerebral injection. Upon in vivo treatment, the antibody was shown to improve cognitive function in experimental amyloidopathy models and to facilitate plaque-associated microglial coverage and activation. CONCLUSION:Thus, we describe a novel monoclonal antibody targeting membrane bound and soluble TREM2, that improves cognitive function by inducing microglial activation and attenuating chronic neuroinflammation.
10.1186/s12974-020-01980-5
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways.
Cell
Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2 variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2 allele, unveiling new options for AD immunotherapy.
10.1016/j.cell.2022.09.033
Mechanism of TREM2/DAP12 complex affecting β-amyloid plaque deposition in Alzheimer's disease modeled mice through mediating inflammatory response.
Cui Xin,Qiao Jun,Liu Sha,Wu Ming,Gu Weiwei
Brain research bulletin
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.
10.1016/j.brainresbull.2020.10.006