Modeling the Aggregation Propensity and Toxicity of Amyloid-β Variants

2015 ◽  
Vol 47 (1) ◽  
pp. 215-229 ◽  
Author(s):  
Manish K. Tiwari ◽  
Kasper P. Kepp
Keyword(s):  
Amyloid Β ◽  
Aggregation Propensity

pH changes the aggregation propensity of amyloid-β without altering the monomer conformation

2014 ◽  
Vol 16 (3) ◽  
pp. 885-889 ◽  
Author(s):  
Debanjan Bhowmik ◽  
Christina M. MacLaughlin ◽  
Muralidharan Chandrakesan ◽  
Prashanth Ramesh ◽  
Ravindra Venkatramani ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Ph Changes ◽  
Aggregation Propensity

Glycation induces conformational changes in the amyloid-β peptide and enhances its aggregation propensity: molecular insights

2016 ◽  
Vol 18 (46) ◽  
pp. 31446-31458 ◽  
Author(s):  
Asis K. Jana ◽  
Kedar B. Batkulwar ◽  
Mahesh J. Kulkarni ◽  
Neelanjana Sengupta
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Advanced Glycation ◽  
Aggregation Propensity

Underlying molecular insights into the higher aggregation propensity of the advanced glycation modified Aβ (or AGE-Aβ) from synchronizedin vitroandin silicostudies.

scholarly journals Amyloid fibrils prepared using an acetylated and methyl amidated peptide model of the α-Synuclein NAC 71–82 amino acid stretch contain an additional cross-β structure also found in prion proteins

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Thomas Näsström ◽  
Per Ola Andersson ◽  
Christian Lejon ◽  
Björn C. G. Karlsson
Keyword(s):  
Amino Acid ◽  
Protein Misfolding ◽  
Prion Proteins ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Full Length ◽  
Aggregation Propensity ◽  
Amino Acid Stretch ◽  
Amidated Peptide ◽  
Β Sheet

Abstract The 71–82 fragment of the non-amyloid-β component (NAC) region of the Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) related protein α-Synuclein, has been reported to be important during protein misfolding. Although reports have demonstrated the importance of this fragment for the aggregation properties of the full-length protein, its exact role in pre-fibrillar oligomerisation, fibrillar growth and morphology has not yet been fully elucidated. Here, we provide evidence that fibrils prepared from an acetylated and methyl amidated peptide of the NAC 71–82 amino acid stretch of α-Synuclein are amyloid and contain, in addition to the cross-β structure detected in the full-length protein fibrils, a cross-β structure previously observed in prion proteins. These results shed light on the aggregation propensity of the NAC 71–82 amino acid stretch of the full-length protein but also the roles of the N- and C-terminal domains of α-Synuclein in balancing this aggregation propensity. The results also suggest that early aggregated forms of the capped NAC 71–82 peptide generated structures were stabilised by an anti-parallel and twisted β-sheet motif. Due to its expected toxicity, this β-sheet motif may be a promising molecular target for the development of therapeutic strategies for PD and DLB.

scholarly journals A Capped Peptide of the Aggregation Prone NAC 71–82 Amino Acid Stretch of α-Synuclein Folds into Soluble β-Sheet Oligomers at Low and Elevated Peptide Concentrations

2020 ◽  
Vol 21 (5) ◽  
pp. 1629 ◽  
Author(s):  
Thomas Näsström ◽  
Jörgen Ådén ◽  
Fumina Shibata ◽  
Per Ola Andersson ◽  
Björn C.G. Karlsson
Keyword(s):  
Amino Acid ◽  
Prion Proteins ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Aggregation Kinetics ◽  
Lewy Neurites ◽  
Aggregation Propensity ◽  
Amino Acid Stretch ◽  
Dynamics Simulations ◽  
Β Sheet

Although Lewy bodies and Lewy neurites are hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), misfolded α-synuclein oligomers are nowadays believed to be key for the development of these diseases. Attempts to target soluble misfolded species of the full-length protein have been limited so far, probably due to the fast aggregation kinetics and burial of aggregation prone segments in final cross-β-sheet fibrils. A previous characterisation study of fibrils prepared from a capped peptide of the non-amyloid β-component (NAC) 71–82 amino acid stretch of α-synuclein demonstrated an increased aggregation propensity resulting in a cross-β-structure that is also found in prion proteins. From this, it was suggested that capped NAC 71–82 peptide oligomers would provide interesting motifs with a capacity to regulate disease development. Here, we demonstrated, from a series of circular dichroism spectroscopic measurements and molecular dynamics simulations, the molecular-environment-sensitive behaviour of the capped NAC 71–82 peptide in a solution phase and the formation of β-sheet oligomeric structures in the supernatant of a fibrillisation mixture. These results highlighted the use of the capped NAC 71–82 peptide as a motif in the preparation of oligomeric β-sheet structures that potentially could be used in therapeutic strategies in the fight against progressive neurodegenerative disorders, such as PD and DLB.

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

2018 ◽  
Vol 19 (8) ◽  
pp. 2415 ◽  
Author(s):  
Daniel Miguel Ángel Villalobos Acosta ◽  
Brenda Chimal Vega ◽  
José Correa Basurto ◽  
Leticia Guadalupe Fragoso Morales ◽  
Martha Cecilia Rosales Hernández
Keyword(s):  
Clinical Trials ◽  
Amyloid Precursor Protein ◽  
Tau Protein ◽  
In Silico ◽  
Catalytic Properties ◽  
Amyloid Β ◽  
Ionic Interactions ◽  
In Vitro Methods ◽  
Aggregation Propensity

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.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

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