Abstract
The amyloid-β 1-42 (Aβ1-42) peptide is produced by proteolytic cleavage of the amyloid precursor protein (APP) by sequential reactions that are catalyzed by γ and β secretases. Aβ1-42, together with the Tau protein are two principal hallmarks of Alzheimer’s disease (AD) that are related to disease genesis and progression. Aβ1-42 possesses a higher aggregation propensity, and it is able to form fibrils via nucleated fibril formation. To date, there are compounds available that prevent Aβ1-42 aggregation, but none have been successful in clinical trials, possibly because the Aβ1-42 structure and aggregation mechanisms are not thoroughly understood. New molecules have been designed, employing knowledge of the Aβ1-42 structure and are based on preventing or breaking the ionic interactions that have been proposed for formation of the Aβ1-42 fibril U-shaped structure. Recently, a new Aβ1-42 fibril S-shaped structure was reported that, together with its aggregation and catalytic properties, could be helpful in the design of new inhibitor molecules. Therefore, in silico and in vitro methods have been employed to analyze the Aβ1-42 fibril S-shaped structure and its aggregation to obtain more accurate Aβ1-42 oligomerization data for the design and evaluation of new molecules that can prevent the fibrillation process.
Highlights
There are several proteins that can form water-insoluble aggregates in different cell lines, which have been generally named amyloids due to the similarity of their features with those reported by Sipe and Cohen, 2000 [1]
In vivo imaging studies and ex vivo histopathological studies only allow us to determine the presence of Aβ with an approximation of its state of aggregation [61,62]; but it is not possible to determine the atomic structure of the Aβ, nor to determine the aggregation stages in vivo, because the experimental conditions of extraction and purification of proteins could modify the quaternary structure [63,64]; it has not been possible to elucidate a quaternary structure for oligomers or fibrils in vivo in the brains of Alzheimer s disease (AD) patients
The most reliable information from the amyloid-β 1-42 (Aβ1-42) structure should be that obtained from AD patients, little information is available about this because once the protein is taken from its natural environment, it can adopt altered structural conformations
Summary
There are several proteins that can form water-insoluble aggregates in different cell lines, which have been generally named amyloids due to the similarity of their features with those reported by Sipe and Cohen, 2000 [1]. In vivo imaging studies and ex vivo histopathological studies only allow us to determine the presence of Aβ with an approximation of its state of aggregation [61,62]; but it is not possible to determine the atomic structure of the Aβ, nor to determine the aggregation stages in vivo, because the experimental conditions of extraction and purification of proteins could modify the quaternary structure [63,64]; it has not been possible to elucidate a quaternary structure for oligomers or fibrils in vivo in the brains of AD patients It has not been confirmed whether the aggregation of Aβ in vitro is similar to those that occur in animal models and in patients. That is the reason that explains why in vitro studies are of great relevance, since when administering synthetic Aβ in vitro in neuronal and astrocyte cultures, as well as in animal models, it reproduces biochemical alterations similar to those determined in brain samples of patients with AD [65]
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