Journal: bioRxiv

Article Title: Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses under Amyloid Stress

doi: 10.64898/2026.04.22.720287

Figure Lengend Snippet: (A) Schematic of the phage display workflow. The extracellular domain of TREM2 was used as the target for selection from a cysteine-constrained cyclic peptide M13 phage library. Four rounds of biopanning, including binding, washing, elution, and amplification, were performed to enrich TREM2-binding clones. (B) Top enriched peptide sequences identified from rounds 2-4. Filled circles indicate detection of a given sequence in the corresponding round, while open circles indicate absence. All sequences conform to a cysteine-constrained cyclic peptide scaffold. (C) Phage ELISA validation of selected peptides. Binding signals are presented as the ratio of signal obtained in TREM2-coated wells relative to control wells lacking protein (E/C). Values above 1 indicate preferential binding to TREM2. Data are shown as mean ± SEM (n=3).

Article Snippet: A 10 μM solution of the His-tagged TREM2 ectodomain (SinoBiological, 11084-H08H) was labeled using the RED-maleimide 2 nd generation dye (NanoTemper, MO-L014) according to the manufacturer’s protocol (labeling buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.5 mM TCEP, 0.05% Tween-20), resulting in a 0.90 μM stock of labeled protein (“TREM2-maleimide-dye”) in storage buffer (HBSP: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20) with a final degree of labeling (DOL) of 0.596.

Techniques: Selection, Binding Assay, Amplification, Clone Assay, Sequencing, Enzyme-linked Immunosorbent Assay, Biomarker Discovery, Control

Journal: bioRxiv

Article Title: Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses under Amyloid Stress

doi: 10.64898/2026.04.22.720287

Figure Lengend Snippet:

Article Snippet: A 10 μM solution of the His-tagged TREM2 ectodomain (SinoBiological, 11084-H08H) was labeled using the RED-maleimide 2 nd generation dye (NanoTemper, MO-L014) according to the manufacturer’s protocol (labeling buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.5 mM TCEP, 0.05% Tween-20), resulting in a 0.90 μM stock of labeled protein (“TREM2-maleimide-dye”) in storage buffer (HBSP: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20) with a final degree of labeling (DOL) of 0.596.

Techniques: Binding Assay

Journal: bioRxiv

Article Title: Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses under Amyloid Stress

doi: 10.64898/2026.04.22.720287

Figure Lengend Snippet: (A) IL-1β secretion in human iPSC-derived microglia following Aβ 1-42 oligomer challenge in the presence of TREM2-6 or TREM2-12 (5, 10, and 25 µM). VG-3927 (5 μM) was used as a positive control. Data are normalized to the Aβ-treated vehicle control and expressed as percent change. (B) Loss of peptide-mediated suppression of IL-1β secretion in TREM2 knockout (KO) microglia confirms TREM2-dependent activity. (C) Modulation of secreted ApoE levels in human microglia following Aβ exposure and peptide treatment (25 µM). ApoE levels are normalized to vehicle-treated controls. Data are presented as mean ± SD (n = 5). Statistical significance was determined by one-way or two-way ANOVA with Dunnett’s post hoc test. ns , not significant; p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), and p < 0.0001 (****) relative to vehicle treatment.

Article Snippet: A 10 μM solution of the His-tagged TREM2 ectodomain (SinoBiological, 11084-H08H) was labeled using the RED-maleimide 2 nd generation dye (NanoTemper, MO-L014) according to the manufacturer’s protocol (labeling buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.5 mM TCEP, 0.05% Tween-20), resulting in a 0.90 μM stock of labeled protein (“TREM2-maleimide-dye”) in storage buffer (HBSP: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20) with a final degree of labeling (DOL) of 0.596.

Techniques: Derivative Assay, Positive Control, Control, Knock-Out, Activity Assay

Journal: bioRxiv

Article Title: Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses under Amyloid Stress

doi: 10.64898/2026.04.22.720287

Figure Lengend Snippet: Quantification of PSD95 levels in human iPSC-derived neuron-microglia co-cultures following Aβ 1-42 oligomer exposure and treatment with TREM2-6 or TREM2-12 (5, 10, and 25 µM). VG-3927 (5 μM) was used as a positive control. PSD95 levels are expressed as percent rescue relative to Aβ-treated vehicle controls. Data are presented as mean ± SD (n = 5). Statistical significance was assessed by one-way ANOVA with Dunnett’s post hoc test. p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), and p < 0.0001 (****) relative to vehicle treatment.

Article Snippet: A 10 μM solution of the His-tagged TREM2 ectodomain (SinoBiological, 11084-H08H) was labeled using the RED-maleimide 2 nd generation dye (NanoTemper, MO-L014) according to the manufacturer’s protocol (labeling buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.5 mM TCEP, 0.05% Tween-20), resulting in a 0.90 μM stock of labeled protein (“TREM2-maleimide-dye”) in storage buffer (HBSP: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20) with a final degree of labeling (DOL) of 0.596.

Techniques: Derivative Assay, Positive Control

Journal: bioRxiv

Article Title: Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses under Amyloid Stress

doi: 10.64898/2026.04.22.720287

Figure Lengend Snippet: (A) Time-dependent root-mean-square deviation (RMSD) of the TREM2 receptor in the free form (cyan line) and in complex with T6 (purple line) and T12 (yellow line) over a 100 ns MD simulation. (B) RMSD of the T6 and T12 over a 100-ns MD simulation.

Article Snippet: A 10 μM solution of the His-tagged TREM2 ectodomain (SinoBiological, 11084-H08H) was labeled using the RED-maleimide 2 nd generation dye (NanoTemper, MO-L014) according to the manufacturer’s protocol (labeling buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.5 mM TCEP, 0.05% Tween-20), resulting in a 0.90 μM stock of labeled protein (“TREM2-maleimide-dye”) in storage buffer (HBSP: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20) with a final degree of labeling (DOL) of 0.596.

Techniques:

Journal: bioRxiv

Article Title: Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses under Amyloid Stress

doi: 10.64898/2026.04.22.720287

Figure Lengend Snippet: B) Structural snapshot clustered from the late stage of the MD simulation of T12 (A) and T6 (B) complexed with TREM2. The receptor is shown in grey cartoon, T12 is shown in blue sticks, and T6 is shown in orange sticks. (C and D) Views of the binding interface between T12 (C) / T6 (D) and TREM2 with the key interacting residues on both sides and yellow dashed lines that demonstrate stable hydrogen bonds and salt bridges.

Article Snippet: A 10 μM solution of the His-tagged TREM2 ectodomain (SinoBiological, 11084-H08H) was labeled using the RED-maleimide 2 nd generation dye (NanoTemper, MO-L014) according to the manufacturer’s protocol (labeling buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.5 mM TCEP, 0.05% Tween-20), resulting in a 0.90 μM stock of labeled protein (“TREM2-maleimide-dye”) in storage buffer (HBSP: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20) with a final degree of labeling (DOL) of 0.596.

Techniques: Binding Assay

Journal: bioRxiv

Article Title: XL-MS and De Novo Protein Design Identified a Common Motif for TREM2 Binding

doi: 10.64898/2026.04.23.720433

Figure Lengend Snippet: (a) SDS-PAGE analysis showing successful cross-linking of the heterodimeric TREM2 ECD /Trx-ApoE3 complex. (b) Representative high-quality MS/MS spectra of inter-protein cross-linked peptides. (c) Bar representation showing intra-protein XLs, inter-protein XLs, and inter-protein self-links. Figure was created using xiNET . ApoE3: light blue (N-terminal region, residues 1-167), light yellow (hinge region, residues 168-205), and pink (C-terminal region, residues 206-299).

Article Snippet: 20 μM Trx-ApoE3 (Sino Biological 10817-H30E) and 20 μM TREM2 ectodomain were incubated for 1 h at 4°C.

Techniques: SDS Page, Tandem Mass Spectroscopy

Journal: bioRxiv

Article Title: XL-MS and De Novo Protein Design Identified a Common Motif for TREM2 Binding

doi: 10.64898/2026.04.23.720433

Figure Lengend Snippet: (a) Mapping intra-ApoE3 cross-links onto the NMR structure (pdb 2L7B). Red line: incompatible XLs with Cβ-Cβ solvent accessible surface distance (SASD) > 35 Å. Blue line: compatible XLs. (b) Filtering the structure ensemble of ApoE3 (Protein Ensemble Database PED07094) by intra-ApoE3 XLs yielded Model 49 with the highest structural compatibility. (c) The best-scoring model of TREM2/ApoE3 complex generated using Haddock. (d) Zoom-in view of the binding interface. ApoE3: light blue (N-terminal region, residues 1-167), light yellow (hinge region, residues 168-205), and pink (C-terminal region, residues 206-299). TREM2 ECD : CDR1(residue 40-42), CDR2(residue 69-72), and CDR3 (residue 88-91).

Article Snippet: 20 μM Trx-ApoE3 (Sino Biological 10817-H30E) and 20 μM TREM2 ectodomain were incubated for 1 h at 4°C.

Techniques: Solvent, Generated, Binding Assay, Residue

Journal: bioRxiv

Article Title: XL-MS and De Novo Protein Design Identified a Common Motif for TREM2 Binding

doi: 10.64898/2026.04.23.720433

Figure Lengend Snippet: (a-m) Design models of mini-proteins in complex with TREM2 ECD (left) and binding affinity determined by microscale thermophoresis (right). Numbers in brackets represent the 68.3% confidence interval calculated by “error-surface projection” .

Article Snippet: 20 μM Trx-ApoE3 (Sino Biological 10817-H30E) and 20 μM TREM2 ectodomain were incubated for 1 h at 4°C.

Techniques: Binding Assay, Microscale Thermophoresis

Journal: Frontiers in Endocrinology

Article Title: TREM2 promotes adipogenesis of PDGFR-α + adipose stem cells but is dispensable for adipose remodeling and metabolic health during diet-induced obesity

doi: 10.3389/fendo.2026.1738472

Figure Lengend Snippet: Trem2 is induced in PDGFR-α + adipocyte progenitors post high-fat diet feeding and associates with a lipid-handling gene signature. (A) t-distributed stochastic neighbor embedding (t-SNE) plot of ASC from eWAT of lean (18 weeks ND) and obese (12 weeks HFD) mice from Gene Expression Omnibus number GSE237143 . The original clustering and cell annotations were retained. Color intensity represents normalized expression levels of Pdgfra (top) and Trem2 (bottom). (B) Uniform Manifold Approximation and Projection (UMAP) plot of FAP from eWAT of lean (18 weeks ND) and obese (18 weeks HFD) mice from Gene Expression Omnibus number GSE160729 . The original clustering and cell annotations were retained. Color intensity represents normalized expression levels of Pdgfra (top) and Trem2 (bottom). (C) Violin plots showing scaled expression levels of the indicated genes ( Cd36, Tyrobp, Apoe, Fabp4, and Plin2 ). Cells were stratified into Trem2 -positive and Trem2 -negative subsets based on expression profiles shown in (A) .

Article Snippet: For the generation of conditional TREM2 knockout mice, Trem2^tm1c(EUCOMM)Wtsi mice (#029853, Jackson Laboratory) carrying floxed alleles of Trem2 were crossed with C57BL/6-Tg(Pdgfrα-cre)1Clc/J mice (#013148, Jackson Laboratory), which express Cre recombinase under the control of the Pdgfrα promoter to achieve adipocyte progenitor–specific Trem2 deletion.

Techniques: Gene Expression, Expressing

Journal: Frontiers in Endocrinology

Article Title: TREM2 promotes adipogenesis of PDGFR-α + adipose stem cells but is dispensable for adipose remodeling and metabolic health during diet-induced obesity

doi: 10.3389/fendo.2026.1738472

Figure Lengend Snippet: TREM2 promotes adipocyte differentiation. (A) Mouse Trem2 and Pparg expression during adipocyte differentiation of stromal vascular fraction cells derived from epididymal white adipose (eWAT), n = 4 per genotype. (B) Representative oil red O staining of adipocytes derived from eWAT 14 days post-differentiation. Magnification is 50 x (C) Pparg , Adipoq and Oil Red O quantification in adipocytes derived from eWAT 14 days post-differentiation, n = 6–7 per genotype. (D) AKT signaling in WT and Trem2 -/- 14-day differentiated adipocytes derived from eWAT, post 20-minute insulin treatment (E) Trem2 , Pparg and Oil Red O levels in adipocytes derived from mouse embryonic fibroblasts (MEF), n = 4 per genotype. (F) Representative oil Red O staining from (E) . Magnification is 5 x. Results in (A, C, E) represent mean ± SEM. All data is representative of 2 independent experiments except data in (C) which is pooled from 2 experiments. Statistical analysis was performed with one-way ANOVA followed by Tukey post-test (A, E) or Student’s T-test (C) . *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Article Snippet: For the generation of conditional TREM2 knockout mice, Trem2^tm1c(EUCOMM)Wtsi mice (#029853, Jackson Laboratory) carrying floxed alleles of Trem2 were crossed with C57BL/6-Tg(Pdgfrα-cre)1Clc/J mice (#013148, Jackson Laboratory), which express Cre recombinase under the control of the Pdgfrα promoter to achieve adipocyte progenitor–specific Trem2 deletion.

Techniques: Expressing, Derivative Assay, Staining

Journal: Frontiers in Endocrinology

Article Title: TREM2 promotes adipogenesis of PDGFR-α + adipose stem cells but is dispensable for adipose remodeling and metabolic health during diet-induced obesity

doi: 10.3389/fendo.2026.1738472

Figure Lengend Snippet: TREM2 deletion in PDGFR-α + pre-adipocytes promotes early adipocyte differentiation. (A) Schematic representation of the Trem2 floxed allele used to generate Trem2 ΔPdgrfα animals. LoxP sites flank exons 2 and 3 of the Trem2 gene. The locations of the forward and reverse primers used to confirm Trem2 deletion are indicated and result in the loss of a 151bp PCR product. (B) Sorting strategy for PDGFR-α+ ASC. ASC are gated as single cells, viable, Lin - (CD45 - CD31 - Ter119 - CD11b - ) cells. Cells were further gated as CD29 + Sca1 + PDGFR-α + . (C) Gel depicting deletion efficiency as determined using PCR on genomic DNA isolated from sorted Lin - CD29 + Sca-1 + PDGFR-α + eWAT ASC from both genotypes of animals. (D, E) Trem2 and Pdgfra levels in adipocytes derived from sorted Lin - CD29 + Sca-1 + PDGFR-α + eWAT ASC from both genotypes of animals for the indicated time points, n = 3–4 per genotype. (F) Pparg levels during early adipocyte differentiation in adipocytes derived from sorted Lin - CD29 + Sca-1 + PDGFR-α + eWAT ASC from both genotypes of animals, n = 3–4 per genotype. (G) Adipoq levels during late adipocyte differentiation in adipocytes derived from sorted Lin - CD29 + Sca-1 + PDGFR-α + eWAT ASC from both genotypes of animals, n = 3–4 per genotype. (H-J) Trem2 , Pparg and Adipoq expression in differentiated adipocytes derived from sorted Lin - CD29 + Sca-1 + PDGFR-α + eWAT ASC from Trem2 -/- mice, n = 3–6 per genotype. Data in (D–J) represent mean ± SEM and data in (H–J) is representative of 2 independent experiments. Statistical analysis was performed with Two-way ANOVA followed by Bonferroni post-test. *P < 0.05, ***P < 0.001, ****P < 0.0001.

Article Snippet: For the generation of conditional TREM2 knockout mice, Trem2^tm1c(EUCOMM)Wtsi mice (#029853, Jackson Laboratory) carrying floxed alleles of Trem2 were crossed with C57BL/6-Tg(Pdgfrα-cre)1Clc/J mice (#013148, Jackson Laboratory), which express Cre recombinase under the control of the Pdgfrα promoter to achieve adipocyte progenitor–specific Trem2 deletion.

Techniques: Isolation, Derivative Assay, Expressing

Journal: Frontiers in Endocrinology

Article Title: TREM2 promotes adipogenesis of PDGFR-α + adipose stem cells but is dispensable for adipose remodeling and metabolic health during diet-induced obesity

doi: 10.3389/fendo.2026.1738472

Figure Lengend Snippet: TREM2 expression in PDGFR-α + pre-adipocytes moderately restrains pre-adipocyte hyperplasia but has no effect on adipose remodeling in obesity. (A) Percentage of PDGFR-α + CD24 + ASC within the lineage-negative pool of eWAT at the indicated times of HFD feeding. n=5-8. (B) Percentage of Ki67 + PDGFR-α + CD24 + ASC three days post HFD. n = 3-4. (C) Percentage of PDGFR-α + CD24 + ASC within the lineage negative pool of eWAT (left), absolute numbers (middle) and percentage Ki67 + (right) therein in both genotypes 3 days post HFD. n=5-6. (D) Body and eWAT weight of Trem2 ΔPdgrfα animals and controls 15 weeks post HFD. n=6-9. (E) Percentage of PDGFR-α + or PDGFR-α + CD24 + ASC within the lineage negative pool of eWAT of Trem2 ΔPdgrfα and littermate control animals 15 weeks post HFD. n=6-9 (F) Representative H&E staining of eWAT in both groups of animals post 15 weeks HFD. (G) Quantification of adipocyte frequency from (F) . n = 13–16 mice per genotype. All data represent mean ± SEM and are representative of 2 independent experiments. Data in A and G is pooled data from 2 independent experiments. Statistical analysis was performed with one-way ANOVA followed by Dunnett post-test (A) or Student’s T-test (B–G) . *P < 0.05, ***P < 0.001, ****P < 0.0001.

Article Snippet: For the generation of conditional TREM2 knockout mice, Trem2^tm1c(EUCOMM)Wtsi mice (#029853, Jackson Laboratory) carrying floxed alleles of Trem2 were crossed with C57BL/6-Tg(Pdgfrα-cre)1Clc/J mice (#013148, Jackson Laboratory), which express Cre recombinase under the control of the Pdgfrα promoter to achieve adipocyte progenitor–specific Trem2 deletion.

Techniques: Expressing, Control, Staining

Journal: Frontiers in Endocrinology

Article Title: TREM2 promotes adipogenesis of PDGFR-α + adipose stem cells but is dispensable for adipose remodeling and metabolic health during diet-induced obesity

doi: 10.3389/fendo.2026.1738472

Figure Lengend Snippet: No influence of TREM2 deletion in PDGFR-α + cells on metabolic health and ATMs. (A) Fasted blood glucose of Trem2 ΔPdgrfα animals and controls 15 weeks post HFD. n=6-9. (B, C) Insulin tolerance (ITT) (B) or oral glucose tolerance test (oGTT) (C) of Trem2 ΔPdgrfα animals and controls 15 weeks post HFD. n=6-9. (D) Serum non-esterified fatty acids (NEFA), triglyceride (TAG), and total cholesterol (T-CHOL) in Trem2 ΔPdgrfα animals and controls 15 weeks post HFD. n=5-8. (E) Gating strategy used to identify ATM populations. ATMs are gated as single cells, viable, CD45 + CD11b + F4/80 + cells. Within the ATM pool the cells were further gated as CD11c + CD206 - or CD9 + or BODIPY + . (F) Percentage of CD11b + F4/80 + ATMs within the CD45 + immune cell pool and absolute macrophage amounts in both genotypes of obese animals, 15 weeks post HFD. n=6-9. (G) Percentage of CD11c + , CD9 + or BODIPY + macrophages within the CD11b + F4/80 + ATM pool in Trem2 ΔPdgrfα animals and controls 15 weeks post HFD. n=6-9. All data represent mean ± SEM and are representative of 2 independent experiments.

Article Snippet: For the generation of conditional TREM2 knockout mice, Trem2^tm1c(EUCOMM)Wtsi mice (#029853, Jackson Laboratory) carrying floxed alleles of Trem2 were crossed with C57BL/6-Tg(Pdgfrα-cre)1Clc/J mice (#013148, Jackson Laboratory), which express Cre recombinase under the control of the Pdgfrα promoter to achieve adipocyte progenitor–specific Trem2 deletion.

Techniques: