Advantages:
- Discovered novel structural interactions between HS and TREM2, associated with neurodegeneration
- High-affinity binding: TREM2 specifically interacts with Heparan Sulfate (HS) modified with 6-O-sulfation and iduronic acid, enabling precise microglial modulation compared to broad-spectrum anti-inflammatory strategies.
- Defined structural requirements: HS chains require a minimum of 10 saccharide units with critical 6-O-sulfation for effective TREM2 binding and ApoE3 uptake, providing clear parameters for therapeutic design ().
- Precision therapy potential: Enables the development of targeted neuroimmunomodulatory therapies for Alzheimer’s disease (AD) and other neurodegenerative disorders by enhancing TREM2-mediated clearance of amyloid-beta lipoproteins, apolipoproteins, phospholipids, and sphingolipids
Summary:
Neurodegenerative diseases, including Alzheimer’s disease (AD), are exacerbated by microglial dysfunction, driven partly by impaired TREM2 signaling. TREM2, a microglial receptor, is critical for phagocytosis, lipid metabolism, and immune modulation under physiological conditions, but its dysfunction—linked to variants like R47H and R62H—accelerates AD pathology by impairing amyloid-beta clearance and promoting neuroinflammation . TREM2 interacts with Heparan Sulfate (HS) as a modulator of microglial function (); however, limited knowledge about the specific binding interactions between TREM2 and HS hinders the ability to design interventions that restore TREM2-mediated neuroprotection in disease states.
Our technology supports novel neuroprotective therapies caused by TRM2 dysfunction by by elucidating the precise HS structural features—6-O-sulfation, iduronic acid, and a minimum chain length of 10 saccharide units—required for high-affinity TREM2 binding (). These interactions are essential for ApoE3 uptake and microglial activation (), offering a foundation for developing precision therapies that enhance TREM2’s physiological roles, such as debris clearance and immune regulation, while counteracting pathological neuroinflammation in AD and other neurodegenerative diseases . Our approach enables targeted neuroimmunomodulation by leveraging these insights, improving disease management and therapeutic outcomes.
LMW HS microarray analysis results indicate essential HS structural requirements for TREM2 binding, including 6S and a minimum chain length of approximately 10 monosaccharide units.
Desired Partnerships:
- Sponsored Research
- Co-Development