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  • br Acknowledgments br Introduction Amyloid

    2024-05-15


    Acknowledgments
    Introduction Amyloid deposit formation is defined by the aggregation of β-sheeted forms of proteins that appear as starch-like amorphous material [1], [2]. Using a Kongo red stain, amyloids show birefringence behavior and an apple-green to reddish multicolor emission. Extracerebral examples of amyloidosis show deposits due to the accumulation of transthyretin or immunoglobulins. Deposition of proteins or protein fragments is also associated with more than 30 diseases [3], [4], [5], including, Parkinson's disease [6], [7], [8], [9], type 2 diabetes [10], [11], dialysis related amyloidosis [12], [13] and Alzheimer's disease (AD) [14], [15], [16], [17]. AD is considered to be the most prevalent and is responsible for 75% of all dementia cases [18]. AD affects more than 35 million people worldwide and the numbers are projected to increase fourfold during the next 30 years [19]. The disorder is characterized by accumulation of intracellular neurofibrillary tangles and extracellular senile plaques [20], [21]. The main component of the extracellular plaques are amyloid-β peptides (Aβ) – mostly 39 to 43 residues long peptides generated from the amyloid precursor protein (APP) via proteolytic cleavage by β- and γ-secretases [22], [23], [24], [25]. The two predominant alloforms of the peptide are Aβ1-40 and Aβ1-42, which have identical sequences except for the last two residues of the Aβ1-42 C-terminus [26]. Although the shorter variant is approximately 10-fold more abundant in blood plasma, Aβ1-42 is the dominant species in amyloid plaques [22], [23], [27]. Furthermore, Aβ1-42 displays notably higher aggregation propensity and exhibits greater toxicity [28], [29], [30]. Several hypotheses have been proposed to explain the toxicity and the role of Aβ peptides in the progression of AD [21], [31], [32]. The two most discussed mechanisms are the metal ion and the amyloid cascade hypotheses. The former suggests that accumulation of Aβ Cobimetinib containing redox sensitive metal ions (Cu2+ or Fe3+) increases the oxidative stress and catalyzes the production of reactive oxygen species (ROS), which are involved in protein and lipid oxidation and can lead to neuronal death [33], [34]. A plethora of studies have shown that both soluble and insoluble Aβ species have relatively high affinities for divalent metal ions. Furthermore, Aβ has the ability to reduce Cu2+ or Fe3+ ions, which can subsequently react with molecular oxygen forming ROS [35], [36], [37], [38]. Several studies have identified small molecules that interfere with the Aβ-metal binding process. These compounds have been shown to alleviate ROS production and neurotoxicity [39], [40], [41], [42], [43]. Undoubtedly, the interactions between metal ions and Aβ peptide are critical to the peptide aggregation pathway and kinetics and can exacerbate the disease symptoms. However, the amyloid cascade hypothesis has received more recognition as the principal mechanism of toxicity [17], [31], [32]. The amyloid cascade hypothesis, formulated quarter-century ago, suggested that Aβ fibrils are the main culprits of AD [44], [45]. Although the hypothesis remains valid, it has been revised to account for the results of more recent studies, which have revealed that Aβ oligomeric species also exhibit neurotoxicity and cause neuronal damage [16], [17], [46]. Aβ oligomers can exhibit toxicity through membrane, intracellular, and receptor-mediated mechanisms [31], [32]. For instance, amyloid oligomers cause synaptic dysfunction by binding to essential synaptic receptors such as the N-methyl-d-aspartate (NMDA) [47], [48], [49] and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) [50], [51] receptor. Furthermore, Aβ oligomers have been shown to interact with the cell membrane, which can lead to channel or pore formation and consequently disruption of Ca2+ homeostasis [52], [53], [54]. However, there is still no consensus on the main toxic species as the precise mechanism of neurotoxicity and the structures of the toxic species remain elusive.