TREM2 in Neurodegenerative Disorders: Mutation Spectrum, Pathophysiology, and Therapeutic Targeting

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• TREM2 (triggering receptor expressed on myeloid cells 2) is a key microglial receptor in the central nervous system.
• It regulates crucial functions including immune response, phagocytosis, and lipid metabolism.
• Dysfunctional TREM2 is implicated in neurodegenerative diseases like Alzheimer's, frontotemporal dementia, and Parkinson's.

Purpose of the Study:

• To review TREM2's structure, function, and the impact of its pathogenic variants.
• To explore the molecular and cellular consequences of TREM2 mutations.
• To highlight emerging therapeutic strategies targeting TREM2 signaling for neurodegenerative diseases.

Main Methods:

• Literature review of TREM2 structure, function, and associated diseases.
• Analysis of molecular and cellular effects of known TREM2 pathogenic variants (e.g., Arg47His, Arg62His).
• Overview of current and developing therapeutic approaches, including antibodies and gene therapies.

Main Results:

• TREM2 mutations impair microglial activation, amyloid aggregate clearance, and promote neuroinflammation.
• Identified consequences include altered ligand binding, protein trafficking, increased shedding, and dysregulated signaling.
• Various therapeutic strategies show promise in preclinical studies for restoring microglial function.

Conclusions:

• TREM2 plays a critical role in neuroprotection, and its dysfunction exacerbates neurodegeneration.
• Therapeutic modulation of TREM2 signaling offers potential for treating neurodegenerative diseases.
• Clinical success depends on addressing disease heterogeneity and mutation-specific responses, optimizing timing and dosage.