disease is associated with brain atrophy and loss of the outer gray matter of the cerebral
cortex. At the cellular level, the histopathology of Alzheimer’s reveals “plaques and
tangles,” where plaques are composed of β-amyloid peptide and tangles are composed
primarily of phosphorylated tau protein. It is believed that the accumulation of neuro-
toxic aggregates of β-amyloid peptide is concomitantly linked with degeneration of
cholinergic pathways in the CNS. This degeneration subsequently leads to progressive
regression of memory and learned functions and to the other symptoms of Alzheimer’s
disease.
Therapeutic approaches to Alzheimer’s disease initially targeted the cholinergic
systems. In early work, drug treatment with either choline replacement or cholinergic
agonists was of negligible value. However, cholinesterase enzyme inhibitors such as
donepezil (4.28), rivastigmine (4.29), and galantamine (4.30) are of definite sympto-
matic value in the treatment of Alzheimer’s disease. By inhibiting the catabolic break-
down of acetylcholine, these agents prolong the effective half-life of acetylcholine as a
neurotransmitter, thereby alleviating some of the symptoms of the disease. About 70%
of people show time-limited improvement in their memory when on these agents.
Unfortunately, these agents are only symptomatic and do not treat the underlying cause,
namely the accumulation of neurotoxic β-amyloid aggregates. Future research in
Alzheimer’s disease is targeting other potential receptors, such as by blocking the
synthesis of β-amyloid by inhibiting the secretase enzyme system involved in the con-
version of amyloid precuror protein to β-amyloid, or by binding to β-amyloid and
inhibiting its aggregation into a neurotoxic form. Since the average age of the popula-
tion is on the increase, the frequency of Alzheimer’s disease is increasing rapidly and
requires urgent attention.
NEUROTRANSMITTERS AND THEIR RECEPTORS 217