Targeting microglia and its relationship with TREM-2 in Alzheimer's disease

Patients with Alzheimer's disease (AD) experience cognitive decline, memory lapses, and impairments in novel object recognition, none of which have been robustly ameliorated by contemporary mainstream treatments based on amyloid beta (A β )-protein hypothesis. The potential involvement of microglial phagocytosis and the correlation between triggering receptors expressed on myeloid cell-2 (TREM2) and microglia in the pathologically excessive accumulation of A β in the hippocampus and cortex is noteworthy. This study investigates the role of TREM2 and its downstream signaling-mediated microglia biological functions, explores the time-dependent features of the TREM2 effect on A β deposition, and analyzes a novel monoclonal antibody (mAb) that promotes the TREM2 expression (4D9, Ab18, and CGX101). Specifically, the study examines recent evidence suggesting TREM2 is a key regulator of microglial function and that loss of TREM2 function increases the risk of Alzheimer's disease. Studies showing TREM2 deficiency results in reduced microglial phagocytosis and lipid transport, leading to amyloid plaque accumulation have been discussed. The study also highlights new mAbs like 4D9 that enhance TREM2 signaling and microglial survival, resulting in reduced amyloid levels in mouse models. Overall, modulating TREM2 presents a promising therapeutic approach to enhancing microglial function and clearance of amyloid aggregates that drive Alzheimer's progression. Further research into the timing and dosing of TREM2-targeting therapies will provide essential insights into their clinical potential and safety.