scholarly journals The conformation of Alzheimer's β peptide determines the rate of amyloid formation and its resistance to proteolysis

1996 ◽  
Vol 314 (2) ◽  
pp. 701-707 ◽  
Author(s):  
Claudio SOTO ◽  
Eduardo M. CASTAÑO
Keyword(s):  
Amino Acid ◽  
Amyloid Β ◽  
Random Coil ◽  
Soluble Form ◽  
Amino Acid Substitutions ◽  
Amyloid Β Peptide ◽  
Amyloid Formation ◽  
Poorly Soluble ◽  
High Concentrations

Amyloid β-peptide (Aβ) is found in an aggregated poorly soluble form in senile or neuritic plaques deposited in the brain of individuals affected by Alzheimer's disease (AD). In addition soluble Aβ (sAβ) is identified normally circulating in human body fluids. In this study we report that synthetic peptides containing the sequences 1–40 and 1–42 of Aβ, and Aβ analogues bearing amino acid substitutions can adopt two major conformational states in solution: (1) an amyloidogenic conformer (Aβac) with a high content of β-sheet and partly resistant to proteases and (2) a non-amyloidogenic conformer (Aβnac) with a random coil conformation and protease-sensitive. The differences in the fibrillogenesis rate and in the protease resistance among the several Aβ peptides studied depend mainly on the relative propensity for adopting the amyloidogenic conformation, which in the absence of external factors is largely conditioned by the primary structure of the peptide. Aβnac containing the sequence 1–40, 1–42 or bearing amino acid substitutions (Dutch variant of Aβ) was protease-sensitive and unable to form a significant amount of amyloid even at high concentrations or after long incubations. The finding of the simultaneous existence of different Aβ conformers with distinct abilities to form amyloid may help to explain why Aβ is found in both soluble and fibrillar forms in vivo.

scholarly journals Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

2021 ◽  
Vol 118 (39) ◽  
pp. e2106210118
Author(s):  
Hebah Fatafta ◽  
Mohammed Khaled ◽  
Michael C. Owen ◽  
Abdallah Sayyed-Ahmad ◽  
Birgit Strodel
Keyword(s):  
Aqueous Phase ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Random Coil ◽  
Neuronal Membrane ◽  
Amyloid Β Peptide ◽  
Main Site ◽  
Neuronal Membranes ◽  
Β Sheet

Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid-β peptides in Alzheimer’s disease. To gain a detailed understanding of the mutual interference of amyloid-β oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid-β (Aβ)42 in the aqueous phase and in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The dimerization in solution is characterized by a random coil to β-sheet transition that seems on pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. As the neurotoxic activity of amyloid oligomers increases with oligomer order, these results suggest that GM1 is neuroprotective against Aβ-mediated toxicity.

scholarly journals Amyloid fibril structure of islet amyloid polypeptide by cryo-electron microscopy reveals similarities with amyloid beta

2020 ◽  
Author(s):  
Christine Röder ◽  
Tatsiana Kupreichyk ◽  
Lothar Gremer ◽  
Luisa U. Schäfer ◽  
Karunakar R. Pothula ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Early Onset ◽  
Critical Role ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Cryo Electron Microscopy

AbstractA critical role of the hormone islet amyloid polypeptide (IAPP) is vividly discussed for Type 2 Diabetes (T2D), where amyloid deposits in pancreatic islets consisting of fibrillar IAPP have been associated with beta cell loss. Here, we applied cryo-electron microscopy to elucidate the structure of IAPP fibrils prepared at physiological pH and reconstructed densities of three dominant polymorphs. An atomic model of the main polymorph comprising residues 13 – 37 in a density map of 4.2 Å resolution reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, which is essential for IAPP amyloidogenicity, forms the protofilament interface together with tyrosine 37 and the amidated C-terminus. The main IAPP fibril polymorph resembles polymorphs of the Alzheimer disease (AD)-associated amyloid-β peptide (Aβ), which is striking in light of the epidemiological link between T2D and AD and reports on IAPP-Aβ cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism S20G with the early-onset AD Arctic mutation E22G of Aβ, rationalize previous data on IAPP fibrils, help to elucidate mechanisms of amyloid formation and toxicity, and support the design of fibril growth inhibitors as well as imaging probes for early detection of IAPP fibrils.

Effects of Single Amino Acid Substitutions on Aggregation and Cytotoxicity Properties of Amyloid β Peptide

2018 ◽  
Vol 25 (2) ◽  
pp. 493-509
Author(s):  
Ana Esther Estrada-Rodríguez ◽  
Donato Valdez-Pérez ◽  
Jaime Ruiz-García ◽  
Alejandro Treviño-Garza ◽  
Ana Miriam Gómez-Martínez ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amyloid Β ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Amyloid Β Peptide

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.

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

scholarly journals Compositional Determinants of Prion Formation in Yeast

2009 ◽  
Vol 30 (1) ◽  
pp. 319-332 ◽  
Author(s):  
James A. Toombs ◽  
Blake R. McCarty ◽  
Eric D. Ross
Keyword(s):  
Amino Acid ◽  
Amino Acid Composition ◽  
Amyloid Formation ◽  
Yeast Prion ◽  
Hydrophobic Residues ◽  
Predictive Methods ◽  
Infectious Proteins ◽  
Β Sheet ◽  
Eukaryotic Genomes

ABSTRACT Numerous prions (infectious proteins) have been identified in yeast that result from the conversion of soluble proteins into β-sheet-rich amyloid-like protein aggregates. Yeast prion formation is driven primarily by amino acid composition. However, yeast prion domains are generally lacking in the bulky hydrophobic residues most strongly associated with amyloid formation and are instead enriched in glutamines and asparagines. Glutamine/asparagine-rich domains are thought to be involved in both disease-related and beneficial amyloid formation. These domains are overrepresented in eukaryotic genomes, but predictive methods have not yet been developed to efficiently distinguish between prion and nonprion glutamine/asparagine-rich domains. We have developed a novel in vivo assay to quantitatively assess how composition affects prion formation. Using our results, we have defined the compositional features that promote prion formation, allowing us to accurately distinguish between glutamine/asparagine-rich domains that can form prion-like aggregates and those that cannot. Additionally, our results explain why traditional amyloid prediction algorithms fail to accurately predict amyloid formation by the glutamine/asparagine-rich yeast prion domains.

scholarly journals In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid β-peptide of APP

2010 ◽  
Vol 48 (1) ◽  
pp. 136-144 ◽  
Author(s):  
D. Allan Butterfield ◽  
Veronica Galvan ◽  
Miranda Bader Lange ◽  
Huidong Tang ◽  
Renã A. Sowell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Methionine 35

scholarly journals Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chu Hsien Lim ◽  
Prameet Kaur ◽  
Emelyne Teo ◽  
Vanessa Yuk Man Lam ◽  
Fangchen Zhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Biological Effects ◽  
Amyloid Β ◽  
Tissue Loss ◽  
Amyloid Β Peptide ◽  
Physical Damage ◽  
Living Tissues

The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

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