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Avoiding Inflammation And Supporting Neurons

Unfortunately, we did not have time to attempt to create all the parts envisioned in our original potential circuit. However, we believe that they are theoretically significant, and so here we explain what more could be done to improve this project of ours, as we work on these improvements after the ‘WikiFreeze’ for the Regional Jamboree of the iGEM competition.

The strength of our system is that the microglial chassis already detect and engage other microglia.

This means that our systems can create proteins in situ to improve the Alzheimer’s disease (AD) state. However, amyloid proteases such as MMP-9 would only have a positive impact on the pathology if the 'Amyloid Hypothesis' is correct, and there is some evidence to suggest that it may not be.

It is thought that AD may be exacerbated into a neurodegenerative condition by the action of microglia themselves, the custodians of the brain. They can inflame the plaque area, and this damages neurons. Therefore, we propose producing a de-activating agent, such as vasoactive intestinal peptide (VIP), BioBrick with an oxidative stress promoter. This means that our genetically engineered microglia (GEM) would activate when it detects a plaque and move towards that plaque. As a GEM approaches, oxidative stress increases so that once near the plaque the de-activating agent would return the GEM and wild-type microglia surrounding the plaque into their resting state, avoiding neuroinflammation. This would stop them from producing amyloid proteases such as neprilysin. However, our MMP-9 BioBrick can ensure that amyloid degradation continues (the positive action of microglia in AD) without inflammation (the negative action of microglia in AD).

It is also thought that AD may initiate due to cell-cycle re-entry on account of a disbalance in neurotrophin signalling. Brain-derived neurotrophic factor (BDNF) is a signal that sustains neurons. If expressed by engineered microglia at plaque localities it could support dying neurons and stop other neurons progressing into an AD state.

Vasoactive Intestinal Peptide

This is a 28 amino acid long secreted neuropeptide. It stimulates heart contractility, vasodilation and glycogenolysis, muscle relaxation in the gastrointestinal tract and lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder (Fahrenkrug and Emson 1982). In the brain, it plays a key role in circadian rhythm control in the hypothalamus. It has been suggested as a therapeutic as it is also known to have a neuroprotective role. Studies have shown that VIP prevents activated microglia inducing the neuroinflammatory conditions that engender and may drive neurodegeneration (Delgado and Ganea March 2003)(Delgado and Ganea Jan 2003).

Brain-Derived Neurotrophic Factor

This is a secreted, 252 amino acid long neurotrophic protein. it is made in the endoplasmic reticulum and secreted from dense core vesicle. it’s assortment into these vesicles is aided by the enzyme carboxypeptidase E. Decreased levels of BDNF have been associated with Alzheimer’s, depression and epilepsy - and so this would be a very useful medical BioBrick. It mainly mediates it effects through membrane protein TrkB. BDNF promotes the neurons’ survival, growth, differentiation and maintenance. It is active at the communicative connections between neurons (synapses), where it helps sustain the synapse and facilitate changes in that synapse’s strength over time, in response to experience. This is called ‘synaptic plasticity’, and is believed to play a key role in learning and memory. A decrease in BDNF could engender cell cycle re-entry (Frade & Lopez-Sanchez 2010) and the senile plaques in AD can disrupt synapses, meaning that they receive less BDNF.