Neuropharmacology: Acetylcholine & Alzheimer's

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Lecture 11 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University.

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  • Neuropharmacology: Acetylcholine & Alzheimer's

    1. 1. Neurochemistry III: Acetylcholine Brian J. Piper, Ph.D.
    2. 2. Objectives• Synthesis• Breakdown• Receptors – nACh – M1 to M5• Neuroanatomy• Alzheimer’s Disease
    3. 3. History1875-1968 • 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. 4. 6.1 Synthesis of acetylcholine (ACh) by choline acetyltransferase • Choline: essential nutrient • Acetyl-CoA: acetyl co-enzyme A • ChAT: choline acetyl (COCH3) transferasehttp://lpi.oregonstate.edu/infocenter/othernuts/choline/
    5. 5. Synthesis of acetylcholine (ACh) by choline acetyltransferase • Choline: essential nutrient • Acetyl-CoA: acetyl co-enzyme A • ChAT: choline acetyl (COCH3) transferasehttp://lpi.oregonstate.edu/infocenter/othernuts/choline/
    6. 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. 7. Acetylcholine Production • VAChT: vesicular Acetylcholine transporter packages ACh • Vesamicol: research drug that blocks VAChTStahl (2001). p. 468
    8. 8. Acetylcholine Inactivation • AChE: acetylcholinesterase, breaks down Ach • ChT: Choline Transporter, recycles choline into presynaptic terminal Stahl (2001). p. 469.
    9. 9. 6.9 Structure of the nicotinic ACh receptor• Ionotropic• Requires 2 ACh• Activated by nicotine• Blocked by curare
    10. 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. 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. 12. Preference?
    13. 13. Preference?
    14. 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. 15. Lesson from Lesion Studies • 192 IgG-Saporin: destroys ACh neurons • Functional Deficits not shown until >70% depletions
    16. 16. 6.6 Cholinergic synapses in the parasympathetic and sympathetic branches of the ANS
    17. 17. Botulism• Infection causes reduced ACh and release• Infants are particularly susceptible
    18. 18. Botulinum Toxin A• Botox is FDA approved for cosmetic purposes• Also used for excessive sweating
    19. 19. Summary
    20. 20. Aloysius ”Alois” Alzheimer• German psychiatrist• Described symptoms + pathology 1864-1913 – Neuronal loss – Plaques – Tangles• Presentation to SW German Psychiatrist meeting ignored but Emil KraeplinCipriani et al. (2011) Neurological Sciences, 32(2), 275-279. Auguste Deter, 1851-1906
    21. 21. 1st, but possibly, atypical case
    22. 22. Healthy Alzheimer’sDisease
    23. 23. AD, external aspect
    24. 24. AD, coronal cross section
    25. 25. Amyloid Plaque• Amyloid Beta Peptide: 40/42 amino acids• Amyloid Plaque: clusters of Beta amyloid +• Neurofibrillary tangles
    26. 26. 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 functionFolstein, Folstein, & McHugh (1975). J Psychiatric Research, 12, 189-198.
    27. 27. Alzheimer’s Vaccine?• Immunization against AB42 produced antibodies• Brain versus BehaviorHolmes et al. (2008) Lancet, 372, 216-223.
    28. 28. Executive Function Test: Trail Making Test: Part A
    29. 29. Trail Making Test: Part B
    30. 30. Executive Function Test 2: Tower of London
    31. 31. Tower of London: Difficult Trial
    32. 32. 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
    33. 33. ApoE & Alzheimer’s DiseaseCorder et al. (1993). Science, 261, 921-3.
    34. 34. Hippocampus, CA1, tau IHCHigher magnification
    35. 35. Current Alzheimer’s Treatments• Alzheimer’s does involve neurodegeneration of cholinergic neurons• Acetylcholinesterase inhibitors (tacrine) have resulted in only modest/brief benefits
    36. 36. Summary AcetylcholineSynthetic EnzymesInactivating EnzymesVesicular TransporterMembrane TransporterWhere in brain (somas)?Ionotropic Receptor(s)Metabotropic Receptor(s)Agonist(s)Antagonist(s)Disease(s)
    37. 37. Self-Test AcetylcholineSynthetic Enzymes Choline AcetyltransferaseInactivating Enzymes AcetylcholinesteraseVesicular Transporter VAChTMembrane Transporter Choline TransporterWhere in brain (somas)? Nucleus basilis, striatumIonotropic Receptor(s) nAChMetabotropic Receptor(s) M1 – M5Agonist(s) Nicotine, MuscarineAntagonist(s) AtropineDisease(s) Myasthenia Gravis, Alzheimer’s?

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