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Author
Paula
Last Updated
7 years ago
License
Creative Commons CC BY 4.0
AbstractAlzheimer’s disease is characterized by death of cholinergic neurons, which secrete the neurotransmitter acetylcholine. This results in a loss of the total amount of acetylcholine circulating in neural networks. Modern drugs target acetylcholinesterase so as to inhibit its function, allowing for increased transmission of acetylcholine in cholinergic synapses. The aim is that an increase in cholinergic activity leads to an increase in cognition. However, these drugs only bind temporarily and have consequential problems that make modern AChE inhibitors of little effect. The main goal of our project is to engineer a snake toxin, fasciculin-II, capable of crossing the blood brain barrier and inhibiting acetylcholinesterase with enough affinity that it increases cholinergic transmission without yielding toxic outcomes. This fasciculin binds to the peripheral acetylcholinesterase found in neuromuscular junctions and causes rapid twitching. Fasciculin-II binds to acetylcholinesterase very tightly with the use of many charged residues and hydrophobic residues and we would like to optimize this interaction so that it may serve a therapeutic purpose in patients of AD.