Part:BBa_K1391010:Experience

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Applications of BBa_K1391010

In the brain of a patient with Alzheimer's disease, beta-amyloid protein oligomers accumulate into plaques, which are responsible for the degenerative symptoms of the disease. In order to diagnose Alzheimer's disease, this system uses beta-amyloid oligomer-specific, transmembrane receptors to detect the presence of beta-amyloid oligomers.

Paired Immunoglobulin-like Receptor B (PirB) is a naturally occurring, transmembrane protein receptor that selectively binds beta-amyloid oligomers. PirB belongs to a family of proteins that bind to MHC1 molecules on antigen presenting cells, and is only expressed in monocytes and B-cells (and at lower levels in dendritic cells and natural killer cells) in mice. When beta-amyloid oligomers bind to the extracellular domain of PirB, it becomes activated and recruits a protein called cofilin (found inside the cell) to its intracellular domain.

In this detection system, PirB was fused to a linker, a TEV protease (TEVp) cleavage site and a transcription factor (in that order) at its intracellular domain. Cofilin was fused to TEV protease. These modifications allowed the manipulation of the natural operational system of PirB such that when beta-amyloid oligomers bind to the receptor (and activate it) the TEV protease on the recruited cofilin cleaves at the TEVp cleavage site. This releases the transcription factor in to the cytosol, where it is guided to the nucleus of the cell and activates some subsequent (reporter or treatment) module.

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