Human Transferrin Receptor Bispecific TREM2 Antibody Creation and Its Insightful Use in Alzheimer's Disease

Authors

Amelia McLaren, DePauw University
June Javens-Wolfe

Files

Document Type

Poster

Publication Date

10-1-2025

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia, affecting an estimated 7.2 million seniors in the United States. AD can develop in the brain for twenty years or more before symptoms appear, such as memory loss, which could enable a diagnostic window for intervention. AD causes neurons to be damaged or destroyed due to the accumulation of amyloid-beta protein fragments and an abnormal form of tau protein. The protein Transmembrane Receptor Expressed by Myeloid Cells, TREM2, is essential in regulating the microglial response to amyloid-beta and tau accumulation in the AD brain. Microglia, the brain’s resident immune cell, has two different paths of activation: one that is anti-inflammatory (M2), and one that is pro-inflammatory (M1). TREM2 is expressed in microglia and myeloid cells. It has a role in regulating microglial inflammatory responses. The TREM2 receptor is connected to DAP12—a signaling adaptor inside the cell that phosphorylates Syk (Spleen Tyrosine Kinase). By creating a TREM2 antibody with an LALAPG mutation, the interaction between the Fc region and the Fc gamma receptor was abolished, which stimulates SYK phosphorylation and phagocytosis. Portions of the antibody were developed from two different companies (e.g., Elana and Denali), who provided the aTREM2 and the hTfR (human transferrin receptor) binding domain, which was inserted in the aTREM2 fc portion. An hTfR receptor allows for two TREM2 antibodies to bind to TREM2 protein and mediate a stronger response via receptor clustering. The hTFR receptor also allows a therapeutic to surpass the blood-brain barrier—hTfR normally transports iron in the body. By inserting hTfR, then inversely, testing could show an elevated production of phospho-Syk using western blots, alphaLISA, and ELISA. Activating Syk matters because it activates the PI3K/AKT pathway that leads to M2 microglia, ultimately protecting those seniors from rapidly declining toward AD.

Department

Neuropharmacology Intern, Indiana Biosciences Research Institute, Indianapolis, IN

Project Mentor

Dr. June Javens-Wolfe (PhD)

Recommended Citation

McLaren, Amelia and Javens-Wolfe, June, "Human Transferrin Receptor Bispecific TREM2 Antibody Creation and Its Insightful Use in Alzheimer's Disease" (2025). Annual Student Research Poster Session. 232.
https://scholarship.depauw.edu/srfposters/232