Neuropharmacology: Acetylcholine & Alzheimer's

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?