Post on 03-Jun-2015
description
Neurochemistry III: Acetylcholine
Brian J. Piper, Ph.D.
Objectives
• Synthesis
• Breakdown
• Receptors– nACh
– M1 to M5
• Neuroanatomy
• Alzheimer’s Disease
History
• Sir Henry Dale (Dale’s law) describes neuron communication as chemical involving Acectylcholine (ACh) in 1914
• Otto Loewi discovers ACh can inhibit the rate of heartbeat in frogs
• Nobel Prize 1936
1875-19681873-1961
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/
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/
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
Acetylcholine Production
• VAChT: vesicular Acetylcholine transporter packages ACh
• Vesamicol: research drug that blocks VAChT
Stahl (2001). p. 468
Acetylcholine Inactivation
• AChE: acetylcholinesterase, breaks down Ach
• ChT: Choline Transporter, recycles choline into presynaptic terminal
Stahl (2001). p. 469.
6.9 Structure of the nicotinic ACh receptor
• Ionotropic
• Requires 2 ACh
• Activated by nicotine
• Blocked by curare
6.4 Myasthenia gravis, an autoimmune disorder
Upto 1:30:http://www.youtube.com/watch?v=XdpW5RMp-T0&feature=related
Prevalence: 10/millionTx: AChE inhibitors,
Muscarinic Acetylcholine Receptors
• Metabotropic
• M1, M2, M3, M4, M5
• Trace amounts of muscarine isolated from Amanita muscaria in 1869
• Found in brain & heart• Antagonist: Atropa Belladonna (atropine)
Amanita muscaria
Inocybe rimosa
Preference?
Preference?
6.7 Anatomy of cholinergic pathways in the brain
• Nucleas basilis: connections to forebrain, important for cognition
• Caudate-Putamen: important for motor function
Lesson from Lesion Studies
• 192 IgG-Saporin: destroys ACh neurons
• Functional Deficits not shown until >70% depletions
6.6 Cholinergic synapses in the parasympathetic and sympathetic branches of the ANS
Botulism
• Infection causes reduced ACh and release
• Infants are particularly susceptible
Botulinum Toxin A
• Botox is FDA approved for cosmetic purposes
• Also used for excessive sweating
Summary
Aloysius ”Alois” Alzheimer
• German psychiatrist
• Described symptoms + pathology– Neuronal loss– Plaques– Tangles
• Presentation to SW German
Psychiatrist meeting ignored but
Emil Kraeplin
Cipriani et al. (2011) Neurological Sciences, 32(2), 275-279.
1864-1913
Auguste Deter, 1851-1906
1st, but possibly, atypical case
Healthy Alzheimer’s Disease
AD, external aspect
AD, coronal cross section
Amyloid Plaque
• Amyloid Beta Peptide: 40/42 amino acids
• Amyloid Plaque: clusters of Beta amyloid +
• Neurofibrillary tangles
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.
Alzheimer’s Vaccine?
• Immunization against AB42 produced
antibodies• Brain versus
Behavior
Holmes et al. (2008) Lancet, 372, 216-223.
Executive Function Test: Trail Making Test: Part A
Trail Making Test: Part B
Executive Function Test 2: Tower of London
Tower of London: Difficult Trial
Genetic Risk Factors
• Apolipoprotein E:– Chromosome 19– 299 amino acids– E3 > E2 > E4
Isoform 112 158
E2 Cysteine Cysteine
E3 Cysteine Arginine
E4 Agrinine Agrinine
ApoE & Alzheimer’s Disease
Corder et al. (1993). Science, 261, 921-3.
Hippocampus, CA1, tau IHCHigher magnification
Current Alzheimer’s Treatments
• Alzheimer’s does involve neurodegeneration of cholinergic neurons
• Acetylcholinesterase inhibitors (tacrine) have resulted in only modest/brief benefits
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)
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?