Site-specific glycosylation patterns on circulating TREM2 ectodomain fragments distinguish senescent from activated microglia states in neurodegeneration. Unlike proteolytic cleavage ratios, this approach leverages differential glycosyltransferase activity (ST6GAL1, MGAT5) that occurs during microglial senescence transitions. Senescent microglia exhibit altered N-linked glycan branching and sialylation on TREM2 before ectodomain shedding, creating distinct glycoform signatures detectable in plasma rather than CSF. The mechanism centers on age-related shifts in ER glycosylation machinery that precede ADAM-mediated shedding, making glycoform analysis upstream of proteolytic processing. This plasma-based assay offers superior clinical accessibility compared to CSF sampling while providing mechanistic insight into microglial aging processes that drive neurodegeneration. Glycan analysis by lectin arrays or mass spectrometry could distinguish homeostatic surveillance (high-mannose, low-sialic acid) from senescence-associated secretory phenotype microglia (complex branched, hypersialylated).
...Curated pathway from expert analysis
flowchart TD
A["TREM2/ADAM10/17<br/>Primary Target"]
B["Biological Process 1<br/>Mechanistic Step A"]
C["Biological Process 2<br/>Mechanistic Step B"]
D["Output Phenotype<br/>Disease Effect"]
A --> B
B --> C
C --> D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for TREM2/ST6GAL1/MGAT5 from GTEx v10.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TREM2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.