The brain relies on a diverse array of cells to maintain its function. Triggering Receptor Expressed on Myeloid cells 2, or TREM2, is a protein found on specific brain cells that plays a part in keeping the brain healthy. Understanding TREM2 and its roles provides insights into how disruptions can lead to neurological conditions.
The Brain’s Immune Cells and TREM2
The brain contains its own dedicated immune cells called microglia. Microglia act as the central nervous system’s primary immune defense, residing throughout the brain and spinal cord, constantly surveying their environment. They extend and retract processes, actively monitoring the functional state of synapses and contacting neurons.
Microglia play diverse roles in maintaining brain health, including clearing cellular debris, damaged neurons, and harmful protein aggregates through phagocytosis. TREM2 is a protein located on the surface of these microglia. It forms a signaling complex with TYROBP (DAP12), which helps activate the cell and initiate responses to injury or disease. TREM2’s functions include sensing and clearing damaged cells or abnormal protein clumps, and it is involved in synaptic pruning.
How TREM2 Influences Brain Health and Disease
When TREM2 does not function correctly, it can have consequences for brain health, linking it to various neurological conditions. Genetic mutations in the TREM2 gene are associated with neurodegenerative diseases. For instance, variants of TREM2 can increase the risk of developing late-onset Alzheimer’s disease (AD). These mutations can impair TREM2’s ability to transmit signals, leading to problems with the microglia’s response to amyloid plaques, a hallmark of Alzheimer’s.
Impaired TREM2 function in Alzheimer’s disease can result in issues with plaque clearance and contribute to chronic inflammation in the brain. Loss of TREM2 function reduces the ability of microglia to respond to these plaques. In addition to Alzheimer’s, homozygous loss-of-function mutations in TREM2 are the cause of Nasu-Hakola disease. This rare, inherited disorder is characterized by progressive early-onset dementia and recurrent bone fractures. Defective signaling through the TREM2-TYROBP complex in microglia leads to widespread abnormalities, contributing to the neurological problems observed.
Targeting TREM2 with Antibodies
Antibodies are protective proteins produced by the immune system that identify and neutralize foreign substances. They circulate in the blood and recognize specific targets, known as antigens, to which they bind. Once an antibody binds to its target, it can either directly neutralize the substance or “tag” it for removal by other immune cells.
A “TREM2 antibody” is an antibody designed to interact with the TREM2 protein. These antibodies are developed to modulate TREM2’s activity, either by enhancing its normal function (activating TREM2) or by blocking an undesirable activity (inhibiting TREM2). For example, some TREM2-activating antibodies aim to boost the protective functions of microglia, such as their ability to clear cellular debris and harmful protein aggregates. Other antibodies might be designed to prevent the shedding of TREM2 from the cell surface, thereby increasing the amount of functional TREM2 available to signal. This modulation of TREM2 activity is a strategy being explored to influence microglial behavior in neurological conditions.
Investigating TREM2 Antibodies for Treatment
Research is exploring TREM2 antibodies as therapeutic agents for neurodegenerative diseases, particularly Alzheimer’s disease. The theoretical benefits of these antibodies include improving microglial function, reducing inflammation, and enhancing the clearance of harmful proteins like amyloid-beta. Activating TREM2 can increase the uptake of amyloid-beta by microglia, which is considered neuroprotective.
Several TREM2 antibodies are currently in early clinical trials, with efforts focused on improving their transport across the blood-brain barrier to reach their targets more effectively. Preclinical studies in mouse models of Alzheimer’s disease pathology have shown that TREM2 antibodies can enhance microglial TREM2 expression and reduce amyloid plaque pathology. A single injection of an activating TREM2 antibody has been shown to induce microglial proliferation and convert them into an active state, with additional injections reducing plaque formation and associated neuronal damage. For example, a humanized monoclonal antibody, AL002, targeting TREM2 has shown promising results in Phase I clinical trials, demonstrating safety and effective target engagement by modulating soluble TREM2 levels and increasing soluble CSF-1R, which suggests heightened microglial activity. This research highlights the promise of TREM2 antibodies as a potential disease-modifying therapy for conditions like Alzheimer’s disease.