1 Alzheimer’s Disease & Acetylcholine Presentation by: Huy Nguyen Chemistry 12B Instructor: Dr. Adamczeski Fall-2006

2 Out line What is Acetylcholine? Synthesis of Acetylcholine How does Acetylcholine work in nervous system Acetylcholine receptors Degradation of Acetylcholine Alzheimer’s disease Drug development Reference

3 What is Acetylcholine? The first known neurotransmitter, discovered in 1920’s. It is the neurotransmitter at nerve-muscle connections and at nervous system synapses. An organic compound: CH 3 CO 2 CH 2 CH 2 N + (CH 3 ) 3

4 Synthesis of Acetylcholine (Ach) Acetylcholine is a simple molecule synthesized from choline and acetyl-CoA through the action of choline acetyltransferase in cholinergic neurons. Acetyl-CoA Choline

5 How does Ach work in nervous system? Action potential reaches the terminal button of a presynaptic neuron. Ca 2+, stimulates the exocytosis of vesicles containing Ach, which is released into the synaptic cleft. Ach reaches the other neuron membrane, then binds to the Ach receptors and activates them to open ion channels to create new action potential.

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7 Acetylcholine receptors Nicotinic receptors: –S – Nicotine: C 10 H 14 N 2

8 Acetylcholine receptors Muscarinic receptors –Muscarine: C 9 H 20 ON +

9 Degradation of Acetylcholine The destruction of Acetylcholine by Acetylcholinesterase and the Reuptake of Choline

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11 Alzheimer’s Disease The cause of Alzheimer's Disease is not fully understood. It is believed there may be genetic (hereditary) factors involved, with a breakdown of proteins resulting in the formation of protein deposits (senile plaques) within the brain. Acetylcholine is required for the normal functioning of the brain cells and, as levels of the chemical decrease, plaques form creating bundles of fibers (neurofibrillary tangles). Alzheimer’s disease is characterized by amyloid plaques (clumps of fibers) and tangles of fibers in brain. Alzheimer’s disease may disrupt normal thinking and memory by blocking the massages transferred through neurons by neurotransmitters. A disorder that primarily affects the elderly and is associated with memory loss. Only Ach and the enzyme Choline acetyltransferase were found to be reduced in the patients with Alzheimer’s disease. – Yahoo! Health Encyclopedia: Alzheimer’s disease Overview

12 Drug development Focus on the development of centrally active muscarinic receptor agonists for the treatment of the Alzheimer’s disease.

13 Drug development Acetylcholinesterase is a tetrameric protein which catalyzes the hydrolysis of Ach. The more easier way to approach the treatment of Alzheimer’s disease is to inhibit the activity of the Acetylcholinesterase in the brain. The general concept to inhibit Acetylcholinesterase is to protect its active – OH group by more active carbonyl compounds.

14 Acetylcholinesterase Inhibitors Inhibitor blocking hydrolysis. Inhibitors that acylate the serine-OH group, forming a carbamyl ester

15 Acetylcholinesterase Inhibitors Donepezil is a good inhibitor and good CNS penetration. Rivastigmine has been approved for use in Europe

16 References