Biophysical analysis of TREM2 interactions reveals a shared binding site for Alzheimer’s disease ligands apoE and oligomeric amyloid beta

The development of new innovative treatments to prevent and ameliorate AD requires knowledge of molecular mechanisms that are critical to neuronal health. The triggering receptor expressed on myeloid cells 2 (TREM2) receptor is part of a signaling complex that modulates inflammatory responses, phagocytosis and cell survival in microglia, resident immune cells in the brain that play a critical role in clearing misfolded aggregates. Examples include neurotoxic aggregates consisting largely of amyloid beta (Ab) and apoliproteinE (apoE). Both molecules have emerged as important signaling ligands for TREM2. Although TREM2 signaling in microglia is generally associated with beneficial outcomes, intense or prolonged signaling may produce overactivated microglia leading to neuronal damage. Such events may also contribute to other diseases such as Parkinson’s or cancers. Furthermore, rare TREM2 variants, most notably R47H and R62H, have been identified that are associated with a significantly increased risk of developing AD. Given these significant roles, TREM2 has emerged as an important yet challenging therapeutic target for AD. Although a number of ligands for TREM2 with relevance to AD have been identified, little is known regarding the molecular details of how TREM2 engages them. Detailed knowledge of the molecular mechanisms underlying TREM2 signaling in microglia is urgently needed to facilitate the development of specific, potent, safe and efficacious therapies for AD that target the TREM2 signaling pathway. The objective of this study was to identify the critical surfaces on TREM2 that mediate interactions with both apolipoproteinE (apoE) and oligomeric amyloid b1‐42 (oAb42) using rigorous structural and biophysical methods.