Microglia, Trem2, and Neurodegeneration
Qian Shi1, Raul A Gutierrez1, Manzoor A Bhat1
1Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
Abstract:
Microglia are a specialized type of neuroimmune cells that undergo morphological and molecular changes through multiple signaling pathways in response to pathological protein aggregates, neuronal death, tissue injury, or infections. Microglia express Trem2, which serves as a receptor for a multitude of ligands enhancing their phagocytic activity. Trem2 has emerged as a critical modulator of microglial activity, especially in many neurodegenerative disorders. Human TREM2 mutations are associated with an increased risk of developing Alzheimer disease (AD) and other neurodegenerative diseases. Trem2 plays dual roles in neuroinflammation and more specifically in disease-associated microglia. Most recent developments on the molecular mechanisms of Trem2, emphasizing its role in uptake and clearance of amyloid β (Aβ) aggregates and other tissue debris to help protect and preserve the brain, are encouraging. Although Trem2 normally stimulates defense mechanisms, its dysregulation can intensify inflammation, which poses major therapeutic challenges. Recent therapeutic approaches targeting Trem2 via agonistic antibodies and gene therapy methodologies present possible avenues for reducing the burden of neurodegenerative diseases. This review highlights the promise of Trem2 as a therapeutic target, especially for Aβ-associated AD, and calls for more mechanistic investigations to understand the context-specific role of microglial Trem2 in developing effective therapies against neurodegenerative diseases.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) on microglia is vital for brain health. Dysregulation of TREM2 exacerbates neuroinflammation, but targeting it offers therapeutic potential for Alzheimer disease (AD).
Area of Science:
- Neuroimmunology
- Neurodegenerative Diseases
Background:
- Microglia, the brain's immune cells, respond to various pathological stimuli.
- TREM2 is a microglial receptor crucial for phagocytosis and modulating neuroinflammation.
- TREM2 dysfunction is linked to increased risk of Alzheimer disease (AD) and other neurodegenerative conditions.
Purpose of the Study:
- To review the molecular mechanisms of TREM2 in microglial function.
- To highlight TREM2's dual role in neuroinflammation and disease-associated microglia.
- To explore TREM2 as a therapeutic target for neurodegenerative diseases, particularly AD.
Main Methods:
- Literature review of recent developments on TREM2 function and therapeutic strategies.
- Analysis of TREM2's role in amyloid-beta (Aβ) clearance and tissue debris management.
- Examination of TREM2's involvement in neuroinflammation and disease progression.
Main Results:
- TREM2 enhances microglial phagocytic activity, aiding in the clearance of Aβ aggregates and debris.
- TREM2 plays a critical role in disease-associated microglia, with dual effects on neuroinflammation.
- Dysregulation of TREM2 can lead to intensified inflammation, posing therapeutic challenges.
Conclusions:
- TREM2 is a promising therapeutic target for neurodegenerative diseases, especially Aβ-associated AD.
- Agonistic antibodies and gene therapy targeting TREM2 represent potential treatment avenues.
- Further mechanistic studies are needed to understand TREM2's context-specific roles for effective therapy development.
