Most of the ideas here are based mostly on this paper: Phagocytic Clearance in Neurodegeneration and the Wikipedia article on microglia. Shinjini is not done reading the said article yet (as of 6/10/14). But she will look into some others the are mentioned at the end.
Why work on macrophages vs neurons:
- Problem of getting circuit into neurons. Macrophages apparently evolve into microglia once in the cell, as mentioned in a paper (paper: Phagocytic Clearance in Neurodegeneration), so would solve the problem of getting the circuit in the brain. (Needs more research.)
- Macrophages are easy to culture, so experiments on it would be more accurate as opposed to mimicking neurons in vitro.
- Macrophages move about, so would have better chances of finding the AB oligomers.
- It would address the destroying plaques already formed problem (paper: Phagocytic Clearance in Neurodegeneration).
- Faulty phagocytosis in microglia are already indicated as potential problem, which is something to look into (paper). Apparently, the problem is microglia being activated for too long, releasing molecules essential for their function, which are also toxic for the neurons. Ideally, our circuit should be able to detect AB before the plaques are formed, avoiding microglia activation.
How the circuit needs to be adjusted for this:
- Macrophages will not be able to reduce the amount of BACE1 already being produced by neurons, which might be a problem. But if a lower ratio of BACE1/BACE2 already works or if higher levels of BACE2 naturally causes BACE1 levels to drop, would solve the problem. However, microglia are indicated to be contributors to the formation of AB, too, so this might still work. Needs research. (paper)
Other things to look into:
- Microglia already have AB receptors. Maybe we should look into that. (paper: Phagocytic Clearance in Neurodegeneration)
Papers Shinjini is looking into (as of 6/10/14):
Phagocytic Clearance in Neurodegeneration
Variant of TREM2 Associated with the Risk of Alzheimer’s Disease
N-APP binds DR6 to cause axon pruning and neuron death via distinct caspases