Modulation of IgG blood-brain barrier permeability by surface-accessible glycan moieties

University Of Washington, Seattle WA

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Abstract

? DESCRIPTION (provided by applicant): Here, we will test the hypothesis that IgG antibody blood-brain barrier permeability will increase in response to elevated surface sialic acid levels. Increasing the blood-brain barrier permeability of antibodies is important because antibody drugs for Alzheimer's Disease and other neurodegenerative disorders remain largely outside the brain after administration. Increasing antibody concentrations in the brain will help the antibodies access their primary therapeutic targets and may also tap into new immune pathways that benefit patients. The project consists of two aims that each address a question below: (1) Does the average IgG blood-brain barrier permeability increase upon addition of IgG sialic acid? (2) Is the blood-brain barrier permeability specific for sialylated IgG higher than fo desiaylated IgG? Both aims will use in vitro blood-brain barrier models to ensure that blood-brain barrier permeability is measured in the absence of other influx and efflux pathways. Aim 1 uses a standard radiolabelling methodology for IgG detection. Aim 2 uses a glycan-specific Surface Plasmon Resonance method to specifically track IgG with surface exposed sialic acid or galactose moieties. Support for this hypothesis will open new avenues for antibody treatment of Alzheimer's Disease and other diseases of the central nervous system.