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.
Highlights
Alzheimer’s disease (AD) is a slowly progressive neurological disorder in which neurodegeneration is believed to begin 20–30 years before clinical onset [1]
Iron homeostasis becomes dysregulated during aging, leading to iron overload, which
Iron homeostasis becomes dysregulated during aging, leading to iron overload, may promote neuroinflammation, protein aggregation, neurodegeneration, and AD dewhich may promote neuroinflammation, protein aggregation, neurodegeneration, and velopment
Summary
Alzheimer’s disease (AD) is a slowly progressive neurological disorder in which neurodegeneration is believed to begin 20–30 years before clinical onset [1]. The are many hypotheses regarding the primary cause of AD, including cholinergic neuron damage, the accumulation of proteins such as amyloid-β (Aβ) in plaques, hyperphosphorylated-tau in neurofibrillary tangles leading to massive loss of synapses, inflammation, the role of butyrylcholinesterase (BChE) in forming Aβ plaques, and oxidative stress. The results from genome-wide association studies (GWAS) have shown that the ε4 allele of APOE is the most potent genetic risk factor for LOAD [18,19,20,21,22], followed by recently detected genetic risk factors that encode proteins involved in microglial function and inflammation, including triggering receptor expressed on myeloid cells-2 (TREM2) [23,24]. Accumulation of Aβ plaques is thought to initiate a pathogenic cascade that leads to synaptic dysfunction and neurodegeneration [42,43]
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