(360u) Molecular Simulations of Protein/Ligand-Mediated Microglial Activation in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease that leads to dementia and is the 6^th leading cause of death in the United States. A hallmark of AD is the buildup of amyloid-beta (A𝛽) plaques in the brain. Once activated, microglia, the key immune effector cells in the brain, seek out and cluster around these plaques, minimizing their neurotoxic effects. These “protective” functions are a result of ligand binding to microglial surface receptor proteins. However, due to the vast number of protein/ligand interactions that influence microglial activation, knowledge of which pathways result in protective microglial phenotypes remains elusive.

Triggering receptor expressed on myeloid cells 2 (TREM2) and lipoprotein lipase (LPL) are two microglial surface proteins that have been repeatedly implicated in the neuropathogenesis of AD. Herein, we describe the use of molecular docking and molecular dynamics (MD) simulations to investigate the interactions between TREM2 and LPL and determine how these interactions modify the cellular response to external stimuli (binding of different AD ligands). Our simulations illustrate novel potential binding mechanisms between TREM2, LPL, and other associated proteins in the cellular signaling pathway, which can then be confirmed experimentally through testing binding sites in HEK 293 and microglial BV-2 cells. Genetic variants of TREM2 related to increased risk for AD are also investigated to provide insights into how changes in these interactions mediate changes in microglial activation and phenotype via differential transmembrane signaling.