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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.
