The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis

Abstract

Alzheimer’s disease (AD), the most common form of dementia in elderly individuals, is marked by progressive neuron loss. Despite more than 100 years of research on AD, there is still no treatment to cure or prevent the disease. High levels of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain are neuropathological hallmarks of AD. However, based on postmortem analyses, up to 44% of individuals have been shown to have high Aβ deposits with no clinical signs, due to having a “cognitive reserve”. The biochemical mechanism explaining the prevention of cognitive impairment in the presence of Aβ plaques is still unknown. It seems that in addition to protein aggregation, neuroinflammatory changes associated with aging are present in AD brains that are correlated with a higher level of brain iron and oxidative stress. It has been shown that iron accumulates around amyloid plaques in AD mouse models and postmortem brain tissues of AD patients. Iron is required for essential brain functions, including oxidative metabolism, myelination, and neurotransmitter synthesis. However, an imbalance in brain iron homeostasis caused by aging underlies many neurodegenerative diseases. It has been proposed that high iron levels trigger an avalanche of events that push the progress of the disease, accelerating cognitive decline. Patients with increased amyloid plaques and iron are highly likely to develop dementia. Our observations indicate that the butyrylcholinesterase (BChE) level seems to be iron-dependent, and reports show that BChE produced by reactive astrocytes can make cognitive functions worse by accelerating the decay of acetylcholine in aging brains. Why, even when there is a genetic risk, do symptoms of the disease appear after many years? Here, we discuss the relationship between genetic factors, age-dependent iron tissue accumulation, and inflammation, focusing on AD.

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“…[ 11 ] For a long time, BChE is ignored as a coregulator of cholinergic neurotransmission or an protector for AChE from damage caused by toxic compounds. [ 12 ] With the progression of AD, the activity of AChE decreases to only 10% to 15% of normal activity, while that of BChE increases, and can thus compensate for the loss in AChE activity. [ 13‐14 ] Besides, there is growing evidence that BChE involved in the onset of AD.…”

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“…It regulates many processes, including memory, learning, attention, and behavior. 6 In detail, ACh exerts excitatory effects at the neuromuscular junction by binding to either nicotinic or muscarinic ACh receptors, thereby initiating its action. The termination of ACh's activity within the synaptic cleft is facilitated by two primary cholinesterases (ChEs), namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).…”

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“…15 BChE produced by reactive astrocytes can worsen cognitive function by accelerating the degradation of acetylcholine in the aging brain. 16 Therefore, developing selective BChE inhibitors is an essential strategy for treating AD, and the main side effects of AChE inhibitors would not be reproduced. 17−20 Pharmacoinformatics approaches, including shape, pharmacophore, and molecular docking, are widely used in drug discovery as they save time, investment and, animal sacrifice.…”