Investigating the therapeutic potential of soluble TREM2 interactions with Transgelin-2 in Alzheimer's disease
Triggering receptor expressed on myeloid cells 2 (TREM2) is a regulator of microglial function in Alzheimer's disease (AD), and its soluble ectodomain (sTREM2) has emerged as a potential neuroprotective factor. Recent work shows that sTREM2 exerts protective effects through direct interaction with neuronal transgelin-2 (TG2) and modulates downstream tau pathology, yet the molecular basis of this…
A study explores the potential of harnessing soluble TREM2 interactions with Transgelin-2 as a therapeutic strategy for Alzheimer's disease. TREM2 is a receptor expressed on myeloid cells, playing a crucial role in regulating microglial function in Alzheimer's disease. Its soluble ectodomain, sTREM2, has shown promise as a neuroprotective factor.
Recent research indicates that sTREM2 interacts directly with neuronal Transgelin-2 (TG2) and influences downstream tau pathology. However, the molecular basis of this interaction remains unclear. To unravel this, the researchers employed all-atom molecular dynamics simulations to define the structural mechanisms of sTREM2-TG2 binding.
They discovered an electrostatically driven interface centered on the TG2 calponin homology domain, which is engaged by a binding motif on sTREM2. This surface is composed of charged anchoring residues flanked by hydrophobic contacts. The study also reveals that the AD-risk TREM2R47H variant maintains a more open, solvent-exposed CDR2 loop, redistributing interfacial contacts while preserving overall binding affinity.
This finding provides a structural explanation for the reports that R47H does not worsen tau pathology in tauopathy models. The insights gained from this study led to the design of optimized sTREM2-derived peptides that surpass a previously reported therapeutic peptide in binding persistence, energetics, and replication of native TG2 contacts.
These findings establish a structure-guided strategy for developing peptide modulators of the sTREM2-TG2 interaction in Alzheimer's disease.
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