Alzheimer’s Disease & Acetylcholine

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: CH3CO2CH2CH2N+(CH3)3 http://www.cas.org/motw/acetylcholinepub.gif

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 http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm

5. How does Ach work in nervous system? • Action potential reaches the terminal button of a presynaptic neuron. • Ca2+, 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. • http://en.wikipedia.org/wiki/intergal-membrane-protine

6. http://en.wikipedia.org/wiki/intergal-membrane-protine

7. Acetylcholine receptors • Nicotinic receptors: • S – Nicotine: C10H14N2 http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm

8. Acetylcholine receptors • Muscarinic receptors • Muscarine: C9H20ON + http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm

9. Degradation of Acetylcholine The destruction of Acetylcholine by Acetylcholinesterase and the Reuptake of Choline http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html

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. http://health.yahoo.com– 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. http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm

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. http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm

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 http://www.cas.org/motw/acetylcholinepub.gif http://web6.duc.auburn.edu/ http://en.wikipedia.org/wiki/intergal-membrane-protine http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html http://www.chemistry.org/ http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm