Acetylcholine is a neurotransmitter synthesized from choline and acetyl-CoA by the enzyme choline acetyltransferase, broken down by acetylcholinesterase, and acts on nicotinic and muscarinic receptors in the central and peripheral nervous systems. Dysfunction of the cholinergic system is implicated in diseases like Alzheimer's and Myasthenia Gravis.

1. Neurochemistry III: Acetylcholine
Brian J. Piper, Ph.D.

2. Objectives
• Synthesis
• Breakdown
• Receptors
– nACh
– M1 to M5
• Neuroanatomy
• Alzheimer’s Disease

3. History
1875-1968
• Sir Henry Dale (Dale’s law) describes 1873-1961
neuron communication as chemical
involving Acectylcholine (ACh) in 1914
• Otto Loewi discovers ACh can inhibit the
rate of heartbeat in frogs
• Nobel Prize 1936

4. 6.1 Synthesis of acetylcholine (ACh) by choline acetyltransferase
• Choline: essential nutrient
• Acetyl-CoA: acetyl co-enzyme A
• ChAT: choline acetyl (COCH3) transferase
http://lpi.oregonstate.edu/infocenter/othernuts/choline/

5. Synthesis of acetylcholine (ACh) by choline acetyltransferase
• Choline: essential nutrient
• Acetyl-CoA: acetyl co-enzyme A
• ChAT: choline acetyl (COCH3) transferase
http://lpi.oregonstate.edu/infocenter/othernuts/choline/

6. Choline During Development
• Choline supplementation shows preclinical
benefits against age related cognitive
decline and against FAS.
• Are there emotional benefits (open-field & FST)
Glenn et al. (2012) Brain Research

7. Acetylcholine Production
• VAChT: vesicular Acetylcholine transporter
packages ACh
• Vesamicol: research drug that blocks VAChT
Stahl (2001). p. 468

8. Acetylcholine Inactivation
• AChE: acetylcholinesterase, breaks down Ach
• ChT: Choline Transporter, recycles choline into presynaptic terminal
Stahl (2001). p. 469.

9. 6.9 Structure of the nicotinic ACh receptor
• Ionotropic
• Requires 2 ACh
• Activated by nicotine
• Blocked by curare

10. 6.4 Myasthenia gravis, an autoimmune disorder
Prevalence: 10/million
Tx: AChE inhibitors,
Upto 1:30:
http://www.youtube.com/watch?v=XdpW5RMp-T0&feature=related

11. Muscarinic Acetylcholine Receptors
• Metabotropic
• M1, M2, M3, M4, M5
Amanita muscaria
• Trace amounts of muscarine
isolated from Amanita muscaria
in 1869
• Found in brain & heart
• Antagonist: Atropa Belladonna Inocybe rimosa
(atropine)

12. Preference?

13. Preference?

14. 6.7 Anatomy of cholinergic pathways in the brain
• Nucleas basilis: connections to forebrain,
important for cognition
• Caudate-Putamen: important for motor
function

15. Lesson from Lesion Studies
• 192 IgG-Saporin: destroys ACh neurons
• Functional Deficits not shown until >70%
depletions

16. 6.6 Cholinergic synapses in the parasympathetic and sympathetic branches of the ANS

17. Botulism
• Infection causes reduced ACh and release
• Infants are particularly susceptible

18. Botulinum Toxin A
• Botox is FDA approved for cosmetic
purposes
• Also used for excessive sweating

19. Summary

21. Aloysius ”Alois” Alzheimer
• German psychiatrist
• Described symptoms + pathology
1864-1913
– Neuronal loss
– Plaques
– Tangles
• Presentation to SW German
Psychiatrist meeting ignored but
Emil Kraeplin
Cipriani et al. (2011) Neurological Sciences, 32(2), 275-279. Auguste Deter, 1851-1906

22. 1st, but possibly, atypical case

23. Healthy Alzheimer’s
Disease

24. AD, external aspect

25. AD, coronal cross section

26. Amyloid Plaque
• Amyloid Beta Peptide:
40/42 amino acids
• Amyloid Plaque: clusters
of Beta amyloid +
• Neurofibrillary tangles

27. Test of Neurocognitive Function
• Mini-Mental Status Exam (MMSE)
– Where are we in?
– Count backwards by 7 starting with 100.
– Remember 3 words.
• Spatial Learning & Memory
• Executive function
Folstein, Folstein, & McHugh (1975). J Psychiatric Research, 12, 189-198.

28. Alzheimer’s Vaccine?
• Immunization against
AB42 produced
antibodies
• Brain versus
Behavior
Holmes et al. (2008) Lancet, 372, 216-223.

29. Executive Function Test: Trail Making Test: Part A

30. Trail Making Test: Part B

31. Executive Function Test 2: Tower of London

32. Tower of London: Difficult Trial

33. Genetic Risk Factors
• Apolipoprotein E: Isoform 112 158
– Chromosome 19
E2 Cysteine Cysteine
– 299 amino acids
– E3 > E2 > E4
E3 Cysteine Arginine
E4 Agrinine Agrinine

34. ApoE &
Alzheimer’s
Disease
Corder et al. (1993). Science, 261, 921-3.

35. Hippocampus, CA1, tau IHC
Higher magnification

37. Current Alzheimer’s Treatments
• Alzheimer’s does involve
neurodegeneration of cholinergic neurons
• Acetylcholinesterase inhibitors (tacrine)
have resulted in only modest/brief benefits

38. Summary
Acetylcholine
Synthetic Enzymes
Inactivating Enzymes
Vesicular Transporter
Membrane Transporter
Where in brain (somas)?
Ionotropic Receptor(s)
Metabotropic Receptor(s)
Agonist(s)
Antagonist(s)
Disease(s)

39. Self-Test
Acetylcholine
Synthetic Enzymes Choline Acetyltransferase
Inactivating Enzymes Acetylcholinesterase
Vesicular Transporter VAChT
Membrane Transporter Choline Transporter
Where in brain (somas)? Nucleus basilis, striatum
Ionotropic Receptor(s) nACh
Metabotropic Receptor(s) M1 – M5
Agonist(s) Nicotine, Muscarine
Antagonist(s) Atropine
Disease(s) Myasthenia Gravis, Alzheimer’s?