Biomedical Engineering Reference
In-Depth Information
16 Acetylcholine
Anders A. Jensen and Povl Krogsgaard-Larsen
CONTENTS
16.1 Alzheimer's Disease............................................................................................................ 263
16.2 Cholinergic Synaptic Mechanisms as Therapeutic Targets ................................................ 266
16.3 Cholinesterases ................................................................................................................... 266
16.3.1 Cholinesterase Inhibitors ....................................................................................... 266
16.3.2 Substrate Catalysis of the AChE and Ligand Binding to It ................................... 269
16.4 Muscarinic ACh Receptors ................................................................................................. 271
16.4.1 mAChR Agonists ................................................................................................... 272
16.4.2 mAChR Antagonists .............................................................................................. 273
16.4.3 Allosteric Modulators of mAChRs........................................................................ 274
16.4.4 Ligand Binding to the mAChR .............................................................................. 274
16.5 Nicotinic ACh Receptors .................................................................................................... 276
16.5.1 nAChR Agonists .................................................................................................... 277
16.5.2 nAChR Antagonists ............................................................................................... 278
16.5.3 Allosteric Modulators of the nAChRs ................................................................... 279
16.5.4 Ligand Binding to the nAChRs ............................................................................. 280
Bibliography .................................................................................................................................. 281
16.1 ALZHEIMER'S DISEASE
Alzheimer's disease (AD) is a degenerative disorder of the human central nervous system (CNS),
which in most cases manifests itself in mid-to-late adult life with progressive cognitive memory and
intellectual impairments, leading invariably to death usually within 7-10 years after the diagnosis.
AD afl icts 2%-3% of individuals at the age of 65, with an approximate doubling of incidence for
every 5 years of age afterward. While age is the dominant risk factor in AD, genetic and epidemio-
logical factors are also important determinants of the development of the disorder.
Clinical diagnosis of AD is based on the progressive impairment of memory and at least one other
cognitive dysfunction, be it “aphasia” (difi culty with language), “apraxia” (difi culty with complex
movements), “agnosia” (difi culty with identifying objects) or impaired executive functioning (making
everyday decisions), and on the ability to exclude other diseases that also cause dementia. The ability
to diagnose AD is very dependent on the progression of the disease but in mid or late stages of the
disease the clinical accuracy in the diagnosis is very high (~90%). However, a diagnosis of AD can
only be made dei nitely based on a direct pathological examination of brain tissue derived from biopsy
or autopsy. The typical macroscopic picture observed in brain tissue from AD patients is massive
atrophy of cortical and hippocampal brain regions, and at the microscopic level a widespread cellular
degeneration and loss of neocortical neurons are observed together with the pathological hallmarks of
the disease: the presence of amyloid “plaques” and neuroi brillary “tangles” (Figure 16.1).
The major component of the amyloid plaques is the amyloid b (Ab 40/42 ) peptide, which is a self-
aggregating, 40/42 amino acids long peptide derived from the proteolytic cleavage of the amyloid
263
 
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