TREM2 is a receptor expressed on the surface of microglia. It responds to changes in the microenvironment and is particularly sensitive to ligands like amyloid beta and neuronal debris. When TREM2 responds to these ligands, it promotes a signalling cascade that elicits SYK phosphorylation and PLC gamma 2 phosphorylation, and this triggers the liberation of second messengers in the cell, such as IP3 and calcium.
These lead to changes in microglial functions, including phagocytosis, migration, survival, and a change in the secretory phenotype. TREM2 is also necessary for the conversion of microglia from the homeostatic state to the disease-associated microglia, and it's believed that upregulation of TREM2 is protective and promotes beneficial microglia signalling.
Emma Mead, Chief Scientific Officer, Alzheimer’s Research UK, Oxford Drug Discovery Institute, University of Oxford, discussed her latest work in identifying and developing peptides to target TREM 2 in Alzheimer’s disease. Bicycle Therapeutics partnered with the Oxford Drug Discovery Institute (ODDI). The ODDI focuses on two distinct mechanistic areas built on the foundations of genome-wide data sets, which point towards changes in organelle dysfunction and neuronal inflammation that lead to an increased risk of developing Alzheimer’s disease.
The partnership led to the development of synthetic Bicycle peptides that function as TREM2 agonists. These peptides are chemically constrained to mimic biologically relevant structures and offer advantages over antibody-based therapies, including lower immunogenicity and oral bioavailability.
Mead explained that her group used a robust screening process and employed methods like phage display, bilayer interferometry, and medicinal chemistry to identify TREM2-binding peptides. Around 300 peptides were screened, and a lead TREM2 agonist was identified. The candidate mediates phagocytosis at low concentrations and receptor internalisation at high concentrations. Moreover, the agonist has high binding affinity and displays strong functional activity in human iPSC macrophages, such as SYK phosphorylation.
Alongside this, the lead TREM2 agonist dose-dependently reduced soluble TREM2, increased secretion of protective chemokines like CCL4, and decreased pro-inflammatory cytokines IL-6. Mead commented that these effects suggest that TREM2 agonism promotes a protective anti-inflammatory microglial phenotype.
Now the team is developing their findings further by mapping the ligand-binding domain. Mead and her group have been using single-chain variable fragments and incubating them in the human iPSC microglia to observe SYK phosphorylation patterns. Finally, efficacy testing is underway in a human iPSC tri-culture model that includes neurons, astrocytes, and microglia, aiming to assess the impact of TREM2 agonism on neuronal health and activity.
