Experimental and Computational Protocols for Studies of Cross-Seeding Amyloid Assemblies

Ren, Baiping; Hu, Rundong; Zhang, Mingzhen; Liu, Yonglan; Xu, Likun; Jiang, Binbo; Ma, Jie; Ma, Buyong; Nussinov, Ruth; Zheng, Jie

doi:10.1007/978-1-4939-7811-3_27

Cited by 11 publications

(8 citation statements)

References 34 publications

(35 reference statements)

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“…298 Furthermore, two review articles have focussed on the interactions of IAPP with the membrane 299,300 and another review deals with experimental and computational methods for investigating crossseeding of Aβ and IAPP. 301 These review articles were published and/or submitted in 2018 so that we focus here on the papers published since 2018. A Web of Science search (performed on March 5, 2020) with the keywords "(amylin OR IAPP) AND simulation*" retrieved a total of 71 papers published in the past two years and two months.…”

Section: Computational Studiesmentioning

confidence: 99%

“…The molecular dynamics (MD) studies of IAPP have been reviewed recently by Moore et al, and in a broad review article that discusses simulations of several amyloidogenic (poly)peptides . Furthermore, two review articles have focused on the interactions of IAPP with the membrane , and another review deals with experimental and computational methods for investigating cross-seeding of Aβ and IAPP . These review articles were published and/or submitted in 2018 so that we focus here on the papers published since 2018.…”

Section: High-resolution Structures Of Iappmentioning

confidence: 99%

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Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

et al. 2021

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The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin and zinc on the mechanism of aggregation of hIAPP. weight reduction was observed. In a phase-1 clinical trial in which AM833 was combined with the GLP-1-agonist Semaglutid, 20 weeks of treatment, participants lost an average of 17.1 % body weight. Overweight and obesity are risk factors for T2D and cardiovascular disease and the presented weight loss exceed reductions observed for GLP-1 and metformin. It should be noted that an IAPP derivative, pramlintide (symlin) is used, in addition to insulin, in patients with insulindependent T1D and T2D that have been difficult to regulate with insulin by a single drug. 42 Cross-correlation with other diseasesEpidemiological studies link diabetes with neurodegenerative diseases, including Alzheimer's disease [43][44][45][46] and Parkinson's disease. [47][48][49] The link is unclear, but the three conditions are multifactorial and have protein aggregation in their pathophysiology in common. If protein aggregation constitutes the link between these diseases, however, still needs to be proven. The Rotterdam study 50 , published in 1999, showed that patients with T2D have an almost doubled risk of developing dementia and Alzheimer's disease (AD). Data from the ULSAM study (Uppsala Longitudinal study of adult men) showed that already a moderate disturbance in the first-phase insulin release at the age of 55 increased the risk of developing AD thirty years later. 51 This suggests that diabetes precedes AD. In fact, another type of diabetes has been proposed [52][53][54] , which is type 3 diabetes (T3DM) which is an AD associated insulin resistance, also described as "brain diabetes phenotype". A considerable number of biophysical studies have shown a close link between the amyloid-forming proteins IAPP and Aβ. [55][56][57][58] IAPP immunoreactivity is present in formic acid brain extracts from patients with AD 59 and exhibited pattern on the western blot ranges from dimers to 16 mers. 60 The laddering pattern suggests that IAPP is present in the Aβ amyloid deposit. Proximity ligation assay (PLA) using two primary antibodies can be applied to determine the co-deposition of proteins. The positive PLA signal obtained after the combination of anti-IAPP and anti-Aβ antibodies points to the co-deposition of IAPP and Aβ in vivo. To confirm that the peptides interact in vivo, hIAPP transgenic mice were injected with preformed fibrils of Aβ followed by high-fat feeding for ten months. 60 Mice injected with preformed Aβ fibrils developed amyloid in 15% of the islets, which is comparable to mice injected with preformed fibrils of proIAPP. In mice injected with preformed IAPP fibrils, IAPP amyloid was found in 24 % of the islets. Control mice injected with fib...

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Section: Computational Studiesmentioning

confidence: 99%

Section: High-resolution Structures Of Iappmentioning

confidence: 99%

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

et al. 2021

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“…During the last decades, computational studies have been extensively used in the investigation, structural elucidation, and design of amyloid self-assembly, − inhibition, − and discovery of amyloid materials. , It was recently demonstrated that computational methods can be used for the design of functional amyloid materials binding to other substances (ions or compounds), in a study focusing particularly on cesium ions . Here, we introduced and advanced our recently published approach to design amyloid materials binding to AD drugs.…”

Section: Discussionmentioning

confidence: 99%

Amyloid Peptide Scaffolds Coordinate with Alzheimer’s Disease Drugs

et al. 2019

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Functional amyloid materials can combine the selfassembly of peptide scaffolds into amyloid fibrils with binding capacities for ions or compounds of pharmaceutical interest, endowed by mutable non-β-sheet-forming residues at the termini. Herein, we report the first to our knowledge amyloid materials, encompassing a GAIIG amyloidogenic core, which bind to Alzheimer's disease (AD) drugs, by mimicking the mechanism by which the same AD drugs bind to enzymes according to experimentally resolved structures, including the target enzyme acetylcholinesterase (AChE). The computationally designed amyloid scaffolds are experimentally shown to coordinate with AD drugs, using two techniques, both in dilute solutions and at higher peptide concentrations, with a higher binding capacity for donepezil and tacrine compared to that for memantine and galantamine. The binding for some of the AD drugs is strong and stable even after extensive subsequent aqueous washings, denoting high capturing efficiency by the designed biomaterials, even after incubation under physiological conditions. Our findings constitute starting points to design novel drug delivery carriers binding to one or combinations of AD drugs (e.g., NMDA and cholinesterase inhibitors).

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“…The amyloid β ( Aβ ) peptides associated with AD, consist of 38 to 43 amino acids chains. 2,3 They are products of β - and γ -secretases acting on the transmembrane amyloid precursor protein (APP). 4–6 Aβ peptides are the main component of extracellular deposits, which are one of the hallmarks of AD.…”

Section: Introductionmentioning

confidence: 99%

“…The amyloid β ( Aβ ) peptides associated with AD consist of 38–43 amino acids chains. , They are products of β- and γ-secretases acting on the transmembrane amyloid precursor protein (APP). − Aβ peptides are the main component of extracellular deposits, which are one of the hallmarks of AD. , Upon cleavage, Aβ monomers are released into the extracellular environment, where they assemble into oligomers, fibrils, and, eventually, into filaments, that are deposited on and interacting in a complex manner with the neural membranes . These filament-like structures are a major component of amyloid plaques.…”

Section: Introductionmentioning

confidence: 99%

Amyloid Fibril Design: Limiting Structural Polymorphism in Alzheimer’s Aβ Protofilaments

et al. 2018

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Nanoscale fibrils formed by amyloid peptides have a polymorphic character, adopting several types of molecular structures in similar growth conditions. This property, evidenced in both experimental (i.e., solid-state NMR) and computational studies, hinders both the structural characterization of Alzheimer’s Aβ amyloid protofilaments and fibrils at a molecular level, as well as the possible applications (i.e., development of drugs or biomarkers) that rely on similar, controlled molecular arrangements of the Aβ peptides in amyloid fibril structures. We have explored the use of several contact potentials for the efficient identification of minimal sequence mutations that could enhance the stability of specific fibril structures while simultaneously destabilizing competing topologies, controlling thus the amount of structural polymorphism in a rational way. We found that different types of contact potentials while having only partial accuracy on their own, lead to similar results regarding ranking the compatibility of wild-type (WT) and mutated amyloid sequences with different fibril morphologies. This property allows exhaustive screening and assessment of possible mutations and the identification of minimal consensus mutations that could stabilize fibrils with the desired topology at the expense of other topology types; a prediction that is further validated using atomistic molecular dynamics with explicit water molecules. We apply this two-step multiscale (i.e., residue and atomistic-level) approach to predict and validate mutations that could bias either parallel or anti-parallel packing in the core Alzheimer’s Aβ 9–40 amyloid fibril models based on solid-state NMR experiments. Besides shedding new light on the molecular origins of a structural polymorphism in WT Aβ fibrils, this approach could also lead to efficient tools for assisting future experimental approaches for amyloid fibril determination, and for the development of biomarkers or drugs aimed at interfering with the stability of amyloid fibrils, as well as for the future design of amyloid fibrils with a controlled (e.g., reduced) level of structural polymorphism.

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Experimental and Computational Protocols for Studies of Cross-Seeding Amyloid Assemblies

Cited by 11 publications

References 34 publications

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

Amyloid Peptide Scaffolds Coordinate with Alzheimer’s Disease Drugs

Amyloid Fibril Design: Limiting Structural Polymorphism in Alzheimer’s Aβ Protofilaments

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