Synthesis and structural characterization of bioactive truncated TREM2
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Henrickson, Brandy, Wijegunawardena, Gayani, Wu, Haifan. Synthesis and structural characterization of bioactive truncated TREM2. -- Fyre in STEM Showcase, 2022.
Dementia affects a person’s cognitive ability and recollection. The most common cause of dementia is Alzheimer’s Disease which features the aggregation of two proteins amyloid-β and tau in the brain. Currently, there is no cure for Alzheimer’s Disease. The search for different treatments has been broken down into different receptors, peptides, and other structures in the brain. One promising drug target is the triggering receptor expressed on myeloid cells 2 (TREM2), which controls the phagocytosis of cellular debris including amyloid-β aggregates by microglia. Previously, a truncated TREM2 peptide was found to be bioactive by promoting microglia survival and activation. We hypothesize that this truncated TREM2 peptide is structured and presents epitopes, parts of antigen molecules, with similarity to the full TREM2 receptor including the outer membrane portion called ectodomain. To test this hypothesis, we chemically synthesized the truncated TREM2 using solid-phase peptide synthesis (SPPS) and formed an intra-molecular disulfide bond to modify the folding structure. The identity of the final product was verified by mass spectrometry. The secondary structures of peptides with or without the disulfide bond were studied by circular dichroism (CD) spectroscopy. We found that truncated TREM2 contains a mixture of beta-sheet and alpha-helix, consistent with that found in the crystal structure of TREM2 ectodomain. The structure is independent on the disulfide bond formation. Interestingly, after disulfide bond formation, this peptide is prone to form thioflavin-T positive aggregates or amyloid-β plaques, an aspect that requires further investigation. Our findings may provide mechanistic understanding of the bioactive truncated TREM2.
Poster and abstract presented at the FYRE in STEM Showcase, 2022.
Research project completed at the Department of Chemistry and Biochemistry.