(416a) Elucidating the Role of TREM2/ApoE Interactions in Microglial Activation and Alzheimer’s Disease with Molecular Simulations

Alzheimer’s disease (AD) is a progressive and ultimately fatal neurodegenerative disease that impacts millions of Americans annually. Changes in brain morphology are the hallmark indicators of disease pathology, but the root cause of AD has yet to be identified. However, a small number of genetic variants have been linked to increased AD risk, including certain isoforms of apolipoprotein E (ApoE) and mutations in the microglial surface protein Triggering receptor expressed on myeloid cells 2 (TREM2). More specifically, ApoE4 and TREM2^R47H are the first and second greatest known genetic risks for late onset AD, respectively, and their direct interaction is thought to have synergistically detrimental impacts on AD pathology. Despite identification of these variants, the mechanisms by which TREM2 and ApoE interact on a molecular level and how these interactions are impacted by the presence of AD risk-associated mutations remain elusive. Herein, we describe the use of molecular docking and molecular dynamics simulations to investigate direct binding interactions between TREM2 and ApoE. These simulations illustrate the impact on ligand binding of several AD-associated mutations on TREM2’s ligand binding patch (R47H, R62H, T96K) and isoforms of ApoE (ApoE2/3/4), in tandem with protective mutations of ApoE (R136S, V236E). Overall, this work provides novel insights into how potential antagonistic protein-protein interactions due to multiple mutations impact key ligand binding events at the microglial cell surface. More broadly, the observed changes in binding suggest possible alterations in downstream microglial signaling/activation, which could have important consequences for the onset and/or progression of AD.