Therapeutic Targeting of Trem2 Signaling in Alzheimer’s Disease: Opportunities and Challenges

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the build-up of amyloid-β (Aβ) plaques, tau neurofibrillary tangles, synaptic impairment, and persistent neuroinflammation. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a microglial surface receptor, has become a crucial modulator of neuroimmune responses in Alzheimer's disease (AD). Infrequent coding mutations in the TREM2 gene, particularly R47H, markedly elevate the risk of late-onset Alzheimer's dementia, underscoring the essential function of TREM2 in disease pathogenesis. TREM2 signalling is crucial for enhancing microglial survival, proliferation, phagocytosis, and the transformation into disease-associated microglia (DAM), which play a role in mitigating amyloid and tau pathology.

Therapeutic techniques designed to augment TREM2 activity have gained traction, encompassing the application of agonistic monoclonal antibodies (e.g., AL002, ATV:TREM2), small chemical modulators, gene therapy methodologies, and metabolic co-targeting strategies to enhance lipid sensing and clearance capabilities. These therapies have demonstrated potential in preclinical models by augmenting microglial activation, increasing plaque compaction, and mitigating tau pathology. Moreover, combination therapy that modulate TREM2 alongside anti-Aβ or anti-tau drugs have exhibited synergistic effects in animal models. Despite these advancements, numerous difficulties persist. TREM2's function is significantly influenced by environment and developmental stage, with its overactivation potentially worsening neuroinflammation or causing adverse effects in advanced Alzheimer's disease. Furthermore, inter-individual variability stemming from genetic background and microglial heterogeneity complicates therapy results.

This review examines the molecular foundation, therapeutic prospects, and translational obstacles of targeting TREM2 in Alzheimer's disease, highlighting the necessity for precision medicine strategies customized to disease stage and patient genotype.

KEYWORDS: TREM2, Alzheimer’s disease, microglia, immunotherapy, neurodegeneration, amyloid-β, tau, personalized medicine.