Abstract 2404 The Relationship Between Acetylcholinesterase and Acetylcholine and its Contribution to Alzheimer's Disease

This is the authors' abstract. We don't add key points for this paper.

Acetylcholinesterase (AChE) is an enzyme that can be found in the synapse of neuromuscular junctions, where the muscle and nerve cells meet (Trang et al, 2023). The enzyme has very high speeds of activity due to its role in discontinuing transmission at the synapse. AChE contains peripheral and catalytic sites in its structure, which act as places for substrates to bind to. AChE carries "a 20 Å deep active site gorge" with a catalytic site at the base. At the place of collision of the gorge, the catalytic and the peripheral sites sits a second peripheral site with countless atomic side chains. Inhibitors of AChE can bind to either the catalytic or the peripheral sites; this is because the peripheral sites guide a majority of the substrates that interact with them to the catalytic sites (Cheung et al, 2013). The job of AChE is to break down Acetylcholine (ACh) into acetic acid and choline (Trang et al, 2023). ACh is a neurotransmitter that sends messages from the brain to the skeletal muscles throughout the body. It is made up of an acetyl group known as acetyl coenzyme A and the nutrient choline. The enzyme choline acetyltransferase stimulates a reaction between the acetyl group and choline creating ACh which is stored at the end of nerve cells. Acetylcholine binds to muscarinic receptors (mAChR) and nicotinic receptors (nAChR) allowing muscle contractions, regulation of heart contractions, maintenance of memory (long and short term) and other various nerve functions (Acetylcholine (ACh): What It Is, Function & Deficiency, 2022). ACh is a substrate to AChE. The peripheral site is a "transitional binding site" to ACh. It has "aromatic amino acids" that establish binding sites with low affinity. A hydrophobic region of the peripheral site traps ACh, bringing it to the catalytic site. The catalytic site has two subsites: the esteratic and anionic sites. In the esteratic site, is a triad of E334, H447, and S203 amino acids. E334 and H447 activate S203 which allows for acylation between S203's hydroxyl group and an oxygen molecule on ACh, forming a covalent bond, resulting in an oxyanion. In the anionic site, a W86 amino acid binds with a trimethylammonium molecule on ACh (Berchansky and Sussman, 2009). When ACh is broken down by AChE, the products are recycled and reused in chemical reactions. However, this is not the case with Alzheimer's disease (AD), which is caused by a deficiency in ACh. This deficiency occurs due to other disorders but is further aggravated by AChE due to its increased hydrolysis of ACh (Acetylcholine (ACh): What It Is, Function & Deficiency, 2022). Due to a deficiency of ACh as a result of AD, there is an upregulation of ACh receptors, nAChR and mAChR, in an effort to increase the chance of ACh interaction with the receptors (Heinemann, Asouline, et al., 1987). The outward effect of the breakdown of the limited supply of ACh by AChE on an AD patient relates to the function of ACh receptors. mAChR sends signals allowing cognitive function and contraction of smooth and cardiac muscle. Therefore, with a deficiency of ACh, symptoms of AD can manifest as memory loss and difficulties in various bodily functions such as decreased skeletal muscle contractions and strength (Chen et al, 2022).