Recent Advances by In Silico and In Vitro Studies of Amyloid-β 1-42 Fibril Depicted a S-Shape Conformation

Acosta, Daniel Miguel Ángel Villalobos; Chimal-Vega, Brenda; Correa-Basurto, José; Morales, Leticia Guadalupe Fragoso; Rosales‐Hernández, Martha Cecilia

doi:10.3390/ijms19082415

Cited by 20 publications

(6 citation statements)

References 101 publications

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“…Moreover, this structure presents two different structural rearrangements, S-shaped and the U-shaped [54,55]. In the last years, several studies have investigated the different behaviour of these polymorphisms and the S-shaped form has demonstrated greater conformational and mechanical stability than the U-shaped form [11,12,56]. Therefore, the S-shaped structure represents the primary target for pharmacological treatments, aimed to reduce the amyloidogenic process and interfere with the amyloid aggregates' stability.…”

Section: Discussionmentioning

confidence: 99%

“…However, the Aβ 42 may arrange also in other polymorphic structures, such as the S-shaped structural rearrangement [55]. Interestingly, recent works have indicated that the S-shaped structure is characterized by superior conformational and mechanical stability with respect to the U-shaped one, suggesting a correlation between structural stability and toxicity [11,12,56].…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization

Muscat

Pallante

Stojceski

et al. 2020

IJMS

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The pursuit for effective strategies inhibiting the amyloidogenic process in neurodegenerative disorders, such as Alzheimer’s disease (AD), remains one of the main unsolved issues, and only a few drugs have demonstrated to delay the degeneration of the cognitive system. Moreover, most therapies induce severe side effects and are not effective at all stages of the illness. The need to find novel and reliable drugs appears therefore of primary importance. In this context, natural compounds have shown interesting beneficial effects on the onset and progression of neurodegenerative diseases, exhibiting a great inhibitory activity on the formation of amyloid aggregates and proving to be effective in many preclinical and clinical studies. However, their inhibitory mechanism is still unclear. In this work, ensemble docking and molecular dynamics simulations on S-shaped Aβ42 fibrils have been carried out to evaluate the influence of several natural compounds on amyloid conformational behaviour. A deep understanding of the interaction mechanisms between natural compounds and Aβ aggregates may play a key role to pave the way for design, discovery and optimization strategies toward an efficient destabilization of toxic amyloid assemblies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization

Muscat

Pallante

Stojceski

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Therefore, the development of relevant experimental models will provide a more complete view of pathogenic processes in AD. Such opportunities may be possible in an in vitro amyloidosis model based on synthetic amyloid peptide application ( Stancu et al, 2014 ; Villalobos Acosta et al, 2018 ; Mango et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor (BDNF) Preserves the Functional Integrity of Neural Networks in the β-Amyloidopathy Model in vitro

Митрошина

Yarkov

Mishchenko

et al. 2020

Front. Cell Dev. Biol.

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Alzheimer’s disease (AD) is a widespread chronic neurodegenerative pathology characterized by synaptic dysfunction, partial neuronal death, cognitive decline and memory impairments. The major hallmarks of AD are extracellular senile amyloid plaques formed by various types of amyloid proteins (Aβ) and the formation and accumulation of intracellular neurofibrillary tangles. However, there is a lack of relevant experimental models for studying changes in neural network activity, the features of intercellular signaling or the effects of drugs on the functional activity of nervous cells during AD development. In this work, we examined two experimental models of amyloidopathy using primary hippocampal cultures. The first model involves the embryonic brains of 5xFAD mice; the second uses chronic application of amyloid beta 1-42 (Aβ1-42). The model based on primary hippocampal cells obtained from 5xFAD mice demonstrated changes in spontaneous network calcium activity characterized by a decrease in the number of cells exhibiting Ca 2+ activity, a decrease in the number of Ca 2+ oscillations and an increase in the duration of Ca 2+ events from day 21 of culture development in vitro . Chronic application of Aβ1-42 resulted in the rapid establishment of significant neurodegenerative changes in primary hippocampal cultures, leading to marked impairments in neural network calcium activity and increased cell death. Using this model and multielectrode arrays, we studied the influence of amyloidopathy on spontaneous bioelectrical neural network activity in primary hippocampal cultures. It was shown that chronic Aβ application decreased the number of network bursts and spikes in a burst. The spatial structure of neural networks was also disturbed that characterized by reduction in both the number of key network elements (hubs) and connections between network elements. Moreover, application of brain-derived neurotrophic factor (BDNF) recombinant protein and BDNF hyperexpression by an adeno-associated virus vector partially prevented these amyloidopathy-induced neurodegenerative phenomena. BDNF maintained cell viability and spontaneous bioelectrical and calcium network activity in primary hippocampal cultures.

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“…Fibrils equivalently to their precursors (oligomers) and protofibrils exhibit polymorphism. Several fibril structures including U-shaped and S-shaped structures have been reported [4,44]. Biophysical techniques provide a limited understanding of the aggregated Aβ species.…”

Section: Discussionmentioning

confidence: 99%

Aggregation Mechanism of Alzheimer’s Amyloid β-Peptide Mediated by α-Strand/α-Sheet Structure

Balupuri

Choi

Kang

2020

IJMS

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Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and a widespread form of dementia. Aggregated forms of the amyloid β-peptide (Aβ) are identified as a toxic species responsible for neuronal damage in AD. Extensive research has been conducted to reveal the aggregation mechanism of Aβ. However, the structure of pathological aggregates and the mechanism of aggregation are not well understood. Recently, experimental studies have confirmed that the α-sheet structure in Aβ drives aggregation and toxicity in AD. However, how the α-sheet structure is formed in Aβ and how it contributes to Aβ aggregation remains elusive. In the present study, molecular dynamics simulations suggest that Aβ adopts the α-strand conformation by peptide-plane flipping. Multiple α-strands interact through hydrogen bonding to form α-sheets. This structure acts as a nucleus that initiates and promotes aggregation and fibrillation of Aβ. Our findings are supported by previous experimental as well as theoretical studies. This study provides valuable structural insights for the design of anti-AD drugs exploiting the α-strand/α-sheet structure.

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Recent Advances by In Silico and In Vitro Studies of Amyloid-β 1-42 Fibril Depicted a S-Shape Conformation

Cited by 20 publications

References 101 publications

The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization

The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization

Brain-Derived Neurotrophic Factor (BDNF) Preserves the Functional Integrity of Neural Networks in the β-Amyloidopathy Model in vitro

Aggregation Mechanism of Alzheimer’s Amyloid β-Peptide Mediated by α-Strand/α-Sheet Structure

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