The human brain, a complex organ, relies on a delicate balance for proper function. Emerging research highlights the importance of specific proteins in maintaining this balance. One such protein, Triggering Receptor Expressed on Myeloid cells 2, or TREM2, is gaining recognition as a significant player in brain health. Understanding its role offers insights into both normal brain function and the origins of neurodegenerative conditions.
What is TREM2?
TREM2 is a receptor protein primarily found on the surface of specialized immune cells called myeloid cells, including macrophages, dendritic cells, and osteoclasts. In the brain, its expression is particularly concentrated on microglia, which are the brain’s resident immune cells. This protein consists of an extracellular V-type immunoglobulin domain, a stalk, a single transmembrane helix, and a short tail inside the cell.
The transmembrane part of TREM2 interacts with an adapter protein called DAP12. This interaction is important for keeping TREM2 stable on the cell membrane and for initiating cell signaling pathways. When TREM2 binds to certain molecules, it activates a series of events inside the cell, involving proteins like spleen tyrosine kinase (Syk) and phospholipase C (PLCĪ³2).
TREM2’s Role in a Healthy Brain
In a healthy brain, TREM2 plays a role in the actions of microglia, which constantly monitor the brain environment. These cells act as a clean-up crew, removing cellular debris and supporting neuronal health. TREM2 helps microglia recognize and clear away waste products like dead cells, damaged myelin, and protein aggregates.
The binding of molecules such as apolipoproteins, including ApoE, to TREM2 enhances the ability of microglia to engulf and process these materials. This process, known as phagocytosis, is important for maintaining brain homeostasis and preventing the accumulation of potentially harmful substances. TREM2 also contributes to microglial survival and proliferation, ensuring that enough of these cells are available to perform their protective functions.
TREM2 and Neurodegenerative Diseases
When TREM2 function is impaired, it can contribute to the progression of neurodegenerative diseases, particularly Alzheimer’s disease (AD). In AD, the brain accumulates abnormal protein deposits, specifically amyloid-beta plaques and tau tangles. Microglia, guided by TREM2, are normally responsible for clearing these harmful aggregates.
If TREM2 function is reduced or altered, microglia become less effective at removing these plaques and tangles. This diminished clearance leads to an increased buildup of amyloid-beta, which contributes to the disease pathology. Microglia with impaired TREM2 function may also adopt a more toxic state, further exacerbating neuronal damage.
Genetic Variations and Disease Risk
Specific genetic changes in the TREM2 gene can alter an individual’s susceptibility to neurodegenerative conditions. For instance, a particular variant known as R47H is associated with an increased risk of developing late-onset Alzheimer’s disease. This genetic alteration leads to an impaired TREM2 protein that has a reduced ability to bind to its target molecules, including amyloid-beta.
This impairment hinders the brain’s immune response, making microglia less effective at clearing harmful protein aggregates. The R47H mutation specifically impairs the protein’s ligand binding domain, leading to the accumulation of amyloid-beta plaques. These genetic variations underscore how even subtle changes in TREM2’s structure can have profound consequences for brain health and disease susceptibility.