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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. 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 [internal link to circuit overview] is that the microglial chassis [internal link to microglia page in background] already detect and engage [internal link to chassis page] amyloid plaques [internal link to neuropathology].

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

It is thought that Alzheimer’s disease (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 [internal link to detection]. This mean that our engineered microglia would activate when it detects a plaque and move towards that plaque. As it approaches, oxidative stress increases so that once near the plaque the de-activating agent would return the engineered cell and wild-type cells 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 [internal link to neuropathology]. 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.


This is a small non-inflammatory chemokine that induces chemotaxis [internal link to chemotaxis page] in macrophages. Microglia originate from a macrophage lineage. It elicits its effect through cell surface chemokine receptor CXCR3. Plaques already attract microglia, but this is partly due to local microglial activation. De-activated GEM will not produce many chemokines, so in order attract more GEM (as well as native microglia) to the plaque site, in order to speed up Aβ clearance.