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.

Keywords: Alzheimer’s disease; BChE; BuChE; IRE; amyloid; butyrylcholinesterase; iron; neuroinflammation; pseudocholinesterase.

Figure 1

Neuroinflammation scheme. Danger signals, like reactive oxygen species (ROS) and LPS, are microglia activators and induce intracellular iron sequestration. LPS stimulates astrocytic hepcidin synthesis, which prevents iron efflux. LPS inhibits TREM-2 expressed on microglial cells, lowering AB clearance. Intracellular iron is bound to cellular ferritin but can dissociate and, via ROS, activate NLRP3 inflammasome, which triggers inflammation and microglial activation, M1 state. M1 microglial release of TNF-α, IL-1α, and C1q, which induce the phagocytosis of neurons and oligodendrocytes by A1 astrocytes, contributing to neurodegeneration and Alzheimer’s disease (AD). A1 astrocytes produce IL-1α, IL-6, and BChE.

Figure 2

Proposed model of BChE expression regulation by iron in the activated glial cells. mRNA sequence analysis revealed putative IRE in the 3′-UTR of BChE (at low quality) and in the 5′-UTR. The Searching for IREs (SIREs) web bioinformatic program was used to predict the 3′-UTR iron-responsive elements in BCHE mRNA [154]. In 5′-UTR, only the consensus IRP binding sequence was found; however, since the expected structure of the 5′-UTR is complex [155], a stem-loop can be formed in a controlled process. Under conditions of high cellular iron, the IRPs cannot bind the IREs. IREs are conserved mRNA motifs. IRPs bound to IREs at the 5′-UTR of mRNA inhibit translation initiation by preventing ribosome binding to the mRNA. The IRPs bound to IREs at the 3′-UTR of mRNA decrease its turnover by preventing endonucleolytic cleavage and mRNA degradation. We suppose that the BChE expression can be positively regulated by iron in the 5′-UTR IRE element and in 3′-UTR by one stem-loop with additional regulator factors as a negative feedback mechanism. In order to validate the predicted IREs, the in vitro functionality has to be determined by competitive EMSA experiments.

Figure 3

Interrelationship of peripheral serum butyrylcholinesterase (BChE) activity and red blood cell (RBC) count. The plasma BChE level shows a positive correlation with RBC count in a large cohort of 1191 individuals. The enzyme activity of a single person is represented by a grey dot. BChE activity was measured by Ellman’s reaction, as described earlier [156].