Biology subjects

Saeb, D.

Publications and source records attributed to Saeb, D..

3 recordsLinked to original sources

bioRxiv2026

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 interaction remains unknown. Here, we use all-atom molecular dynamics simulations to define the structural mechanisms of sTREM2-TG2 binding. We identify an electrostatically driven interface centered on the TG2 calponin homology domain. This surface is engaged by a binding motif on sTREM2 in which charged anchoring residues are flanked by hydrophobic contacts. We further show that the AD-risk TREM2R47H variant maintains a more open, solvent-exposed CDR2 loop that redistributes interfacial contacts while preserving overall binding affinity, offering a structural explanation for reports that R47H does not exacerbate tau pathology in tauopathy models. Leveraging these insights, we design optimized sTREM2-derived peptides that outperform a previously reported therapeutic peptide in binding persistence, energetics, and recapitulation of native TG2 contacts, supporting engagement at the epitope through which sTREM2 suppresses tau phosphorylation. Taken together, our results define a mechanistic framework for the sTREM2-TG2 axis in AD and establish a structure-guided strategy for developing peptide modulators of this interaction.

bioengineering↗

bioRxiv2026

hMSCs for Osteocyte-like Cell Networks within Strain-Stiffening Bottlebrush Polymer Hydrogels

Bone formation and remodeling depend on dynamic biochemical and biomechanical signaling from the collagen-rich osteoid that precedes mineralization, yet the role of osteoid nonlinear mechanics in regulating osteocyte-like network formation remains poorly understood. Here, we engineered a synthetic bottlebrush polymer hydrogel (BB) that mimics key mechanical features of osteoid and compared it to collagen type-I (Col1) matrices with matched shear modulus (~70 Pa) and strain-stiffening behavior. Human bone marrow-derived mesenchymal stem/stromal cells (hMSCs) were cultured for 28 days in growth (GM) or osteogenic media (OM) to examine network formation, and functional connectivity using live cell fluorescence recovery after photobleaching. hMSCs cultured in BB networks and OM showed upregulation of early osteocyte markers compared to Col1. We find that strain-stiffening materials with minimal stress relaxation promote osteocyte-like cell differentiation with functional connectivity, establishing osteoid-mimetic BB hydrogels as a promising matrix to study human osteocytogenesis and osteocyte mechanotransduction in vitro.

bioengineering↗

bioRxiv2024

The flexible stalk domain of sTREM2 modulates its interactions with phospholipids in the brain

The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimers disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in modulating the dynamics of the Ig-like domain and altering the accessibility of canonical ligand binding sites. We identified a novel ligand binding site on sTREM2, termed the Expanded Surface 2, which emerges due to competitive binding of the stalk with the Ig-like domain. Additionally, we observed that the stalk domain itself functions as a site for ligand binding, with increased binding frequency in the presence of R47H. This suggests that sTREM2s neuroprotective role in AD may, at least in part, arise from the stalk domains ability to rescue dysfunctional ligand binding caused by AD-risk mutations. Lastly, our findings indicate that R47H-induced dysfunction in TREM2 may result from both diminished ligand binding due to restricted complementarity-determining region 2 loop motions and an impaired ability to differentiate between ligands, proposing a novel mechanism for loss-of-function. In summary, these results provide valuable insights into the role of sTREM2 in AD pathology, laying the groundwork for the design of new therapeutic approaches targeting (s)TREM2 in AD.

bioengineering↗