MIT iGEM 2014

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Project Description

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Alzheimer's disease is a neurodegenerative disease that afflicts nearly 30 million people worldwide. It is characterized by the aggregation of beta-amyloid oligomers and plaques which cause neuron death and inhibit the proper functioning of surviving neurons. There is no definitive molecular detection or treatment mechanisms for the disease; this is what MIT iGEM 2014 seeks to address in our project, The Diagnosis and Treatment of Alzheimer's Disease.
We built two systems to detect Alzheimer's disease in the brain. The first is a detection system for beta-amyloid, in which extracellular oligomers bind to a transmembrane receptor and result in the release of a transcription factor. For this detection system, we employed two different beta-amyloid specific receptors: LilrB2, a protein receptor found naturally occuring in the human immune system; and a synthetic B-cell receptor we designed based on an antibody that recognizes beta-amyloid.
The second system detects the disease using a different biomarker: an intracellular microRNA profile, specific to neurons affected by Alzheimer's. Cells express different miRNAs according to their cell type and disease state. It is known that several miRNAs are up- or down- regulated in “Alzheimer’s state” neurons compared to healthy ones. Using this knowledge, we have built 2 sensors: a "low" sensor to detect miRNAs that are down-regulated compared to healthy neurons, and a "high" sensor to detect miRNAs which are up-regulated. These sensors can then be combined to sense the specific combination of miRNAs that indicate a neuron in the Alzheimer's state.
Finally, we designed a treatment module that could be activated by one of the detection modules to actually treat Alzheimer's disease. In order to treat the disease, we aim to reduce the number of beta-amyloid oligomers and plaques in the brain. We do this by expressing a beta-amyloid-degrading enzyme – BACE2 – and down-regulating an endogenous enzyme that is crucial for beta-amyloid formation – BACE1. This module can be coupled to any of our diagnostic modules to form an integrated circuit to diagnose and treat Alzheimer's disease.

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