Title:Butyrylcholinesterase as a Diagnostic and Therapeutic Target for Alzheimer’s Disease
Volume: 13
Issue: 10
Author(s): Sultan Darvesh
Affiliation:
Keywords:
Acetylcholinesterase, amyloid, cholinergic, dementia, neuroimaging, phenothiazines.
Abstract: The serine hydrolase butyrylcholinesterase (BChE), like the related enzyme
acetylcholinesterase (AChE), co-regulates metabolism of the neurotransmitter acetylcholine.
In the human brain BChE is mainly expressed in white matter and glia and in distinct
populations of neurons in regions that are important in cognition and behavior,
functions compromised in Alzheimer’s disease (AD). AD is a neurodegenerative disorder
causing dementia with no cure nor means for definitive diagnosis during life. In AD,
BChE is found in association with pathology, such as β-amyloid (Aβ) plaques, particularly
in the cerebral cortex where BChE is not normally found in quantity. Up to 30% of
cognitively normal older adults have abundant Aβ deposition in the brain. We have designed
an imaging agent that can detect, through autoradiography, BChE-associated Aβ
plaques in the cerebral cortex of AD brains, but does not visualize Aβ plaques in brains
of cognitively normal individuals. Furthermore, in an AD mouse model with BChE gene knocked out, there
are up to 70% fewer fibrillar Aβ brain plaques, suggesting diminished BChE activity could prove beneficial
as a curative approach to AD. To that end, we have examined numerous N-10-carbonyl phenothiazines that
are specific inhibitors of human BChE, revealing important details of the enzyme’s active site gorge. These
phenothiazines can be designed without potential side effects caused by neurotransmitter receptor interactions.
In conclusion, BChE is potentially an important target for diagnosis and treatment of AD.
