Alzheimer’s disease (AD) is the leading cause of dementia, inflicting an immense financial and emotional burden. The two hallmarks of Alzheimer’s disease (AD) are the extracellular aggregation of amyloid beta (Aβ) protein into amyloid plaques in the brain and chronic inflammation.
Triggering receptor expressed on myeloid cells-2 (TREM2) is a key protein that mediates inflammatory response in AD. Mutations in TREM2 have been linked to a three-fold increase in the risk of AD. Among the many ligands of TREM2, its interactions with Aβ are pivotal for understanding the microglial response in AD. In addition, individual interactions of TREM2 and Aβ with glycosaminoglycans (GAGs) have been reported to mediate AD pathology.
We hypothesize that cell-surface GAGs such as heparan sulfate interact with TREM2, mediating its interaction with Aβ. These interactions eventually lead to the phagocytosis of amyloid deposits by microglia. Mutations in TREM2 adversely affect these interactions leading to insufficient microglial response. In this study, we aim to decipher the role of these dynamic interactions of TREM2 and Aβ in the presence of glycosaminoglycans.
We are approaching this in vitro by using purified proteins and employing various biochemical techniques, such as aggregation-kinetics assays, solution NMR, and electron microscopy. Furthermore, we have studied the structural properties of TREM2 using analytical ultracentrifugation (AUC) and small-angle X-ray scattering (SAXS) techniques. Considering heparin as a model GAG, we show that it interacts with monomeric Aβ and increases Aβ fibrillization. We find that TREM2 strongly inhibits Aβ aggregation, whereas heparin blocks this effect, potentially by binding to the same site as Aβ on TREM2.
Our study will provide a detailed understanding of the structural properties of TREM2, and its key interactions underlying AD and may help in developing therapeutic strategies in the future.