scholarly journals Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa

2021 ◽  
Vol 22 (3) ◽  
pp. 1225
Author(s):  
Ziao Fu ◽  
William E. Van Nostrand ◽  
Steven O. Smith
Keyword(s):  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Aβ Oligomers ◽  
Dominant Component ◽  
Fibril Structure ◽  
Predominant Component ◽  
Aβ Aggregation ◽  
Aβ Fibrils ◽  
Soluble Aβ Oligomers ◽  
Β Sheet

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each.

scholarly journals Au23(CR)14 nanocluster restores fibril Aβ’s unfolded state with abolished cytotoxicity and dissolves endogenous Aβ plaques

2019 ◽  
Vol 7 (4) ◽  
pp. 763-774 ◽  
Author(s):  
Wenkang Zhang ◽  
Guanbin Gao ◽  
Zhongjie Ma ◽  
Zhuoying Luo ◽  
Meng He ◽  
...  
Keyword(s):  
Brain Slices ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Peptides ◽  
Unfolded State ◽  
Good Biocompatibility ◽  
Aβ Fibrils ◽  
Soluble Aβ Oligomers ◽  
Β Sheet

Abstract The misfolding of amyloid-β (Aβ) peptides from the natural unfolded state to β-sheet structure is a critical step, leading to abnormal fibrillation and formation of endogenous Aβ plaques in Alzheimer's disease (AD). Previous studies have reported inhibition of Aβ fibrillation or disassembly of exogenous Aβ fibrils in vitro. However, soluble Aβ oligomers have been reported with increased cytotoxicity; this might partly explain why current clinical trials targeting disassembly of Aβ fibrils by anti-Aβ antibodies have failed so far. Here we show that Au23(CR)14 (a new Au nanocluster modified by Cys-Arg (CR) dipeptide) is able to completely dissolve exogenous mature Aβ fibrils into monomers and restore the natural unfolded state of Aβ peptides from misfolded β-sheets. Furthermore, the cytotoxicity of Aβ40 fibrils when dissolved by Au23(CR)14 is fully abolished. More importantly, Au23(CR)14 is able to completely dissolve endogenous Aβ plaques in brain slices from transgenic AD model mice. In addition, Au23(CR)14 has good biocompatibility and infiltration ability across the blood–brain barrier. Taken together, this work presents a promising therapeutics candidate for AD treatment, and manifests the potential of nanotechnological approaches in the development of nanomedicines.

scholarly journals Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

2021 ◽  
Vol 118 (4) ◽  
pp. e2023089118 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Kent R. Thurber ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Molecular Conformations ◽  
Layered Architecture ◽  
Fibril Structure ◽  
Aggregation Inhibitors ◽  
Aβ Fibrils ◽  
Β Sheet

Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer’s disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

scholarly journals Borrelidin from Saltern-Derived Halophilic Nocardiopsis sp. Dissociates Amyloid-β and Tau Fibrils

2020 ◽  
pp. 1-7
Author(s):  
Jisu Shin ◽  
Seung-Hoon Yang ◽  
Young Eun Du ◽  
Keunwan Park ◽  
DaWon Kim ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Thioflavin T ◽  
Drug Candidate ◽  
Ht22 Cells ◽  
Aβ Aggregation ◽  
Actinomycete Strain ◽  
Direct Dissociation ◽  
Aβ Fibrils ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-β (Aβ) and tau, leading to neuronal and cognitive dysfunction. Clearance of either Aβ or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that Aβ and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together. Objective: We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble Aβ and tau aggregates through in vitro assessments. Methods: We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with Aβ fibrils. Then, anti-cytotoxic, anti-Aβ, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis. Results: When HT22 cells were exposed to Aβ aggregates, the treatment of borrelidins alleviates the Aβ-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the Aβ aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates Aβ aggregates but also directly regulates tau aggregation. Conclusion: Borrelidin dissociates insoluble Aβ and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-Aβ or anti-tau immunotherapy for clearance of both aggregates.

scholarly journals Analysis of anticoagulants for blood-based quantitation of amyloid β oligomers in the sFIDA assay

2017 ◽  
Vol 398 (4) ◽  
pp. 465-475 ◽  
Author(s):  
Kateryna Kravchenko ◽  
Andreas Kulawik ◽  
Maren Hülsemann ◽  
Katja Kühbach ◽  
Christian Zafiu ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Limit Of Detection ◽  
Amyloid Β ◽  
Distribution Analysis ◽  
Aβ Oligomers ◽  
Quantitative Measurements ◽  
Suitable Parameter ◽  
Edta Plasma ◽  
Soluble Aβ Oligomers ◽  
Parameter Values

Abstract Early diagnostics at the preclinical stage of Alzheimer’s disease is of utmost importance for drug development in clinical trials and prognostic guidance. Since soluble Aβ oligomers are considered to play a crucial role in the disease pathogenesis, several methods aim to quantify Aβ oligomers in body fluids such as cerebrospinal fluid (CSF) and blood plasma. The highly specific and sensitive method surface-based fluorescence intensity distribution analysis (sFIDA) has successfully been established for oligomer quantitation in CSF samples. In our study, we explored the sFIDA method for quantitative measurements of synthetic Aβ particles in blood plasma. For this purpose, EDTA-, citrate- and heparin-treated blood plasma samples from five individual donors were spiked with Aβ coated silica nanoparticles (Aβ-SiNaPs) and were applied to the sFIDA assay. Based on the assay parameters linearity, coefficient of variation and limit of detection, we found that EDTA plasma yields the most suitable parameter values for quantitation of Aβ oligomers in sFIDA assay with a limit of detection of 16 fM.

scholarly journals Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ladan Amin ◽  
David A. Harris
Keyword(s):  
Amyloid Β ◽  
Super Resolution ◽  
Structural Motif ◽  
Aβ Oligomers ◽  
Surface Receptors ◽  
Molecular Features ◽  
Molecular Determinant ◽  
Receptor Interactions ◽  
Aβ Fibrils ◽  
Super Resolution Microscopy

AbstractSeveral cell-surface receptors for neurotoxic forms of amyloid-β (Aβ) have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating Alzheimer’s disease pathology have remained uncertain. Here, we used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, PrPC, specifically inhibits the polymerization of Aβ fibrils by binding to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrPC binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrPC. Our results suggest that receptors may trap Aβ oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant on these assemblies, thereby initiating a neurotoxic signal.

scholarly journals Cu-Based Turn-on Fluorescent Sensors for Cu-rich Amyloid β Aggregates

2021 ◽  
Author(s):  
Yiran Huang ◽  
Liang Sun ◽  
Liviu M. Mirica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fluorescence Imaging ◽  
Protein Misfolding ◽  
Picolinic Acid ◽  
Amyloid Β ◽  
Fluorescent Sensors ◽  
Aβ Oligomers ◽  
Turn On ◽  
Aβ Aggregation

<div>Protein misfolding and metal dishomeostasis are two key</div><div>pathological factors of Alzheimer’s disease. Previous studies have showed that Cu‐mediated Aβ aggregation pathways lead to formation of neurotoxic Aβ oligomers. Herein, we reported a series of picolinic acid‐based Cu‐activatable sensors, which can be used for the fluorescence imaging of Cu‐rich Aβ aggregates.</div>

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals Aβ42 fibril formation from predominantly oligomeric samples suggests a link between oligomer heterogeneity and fibril polymorphism

2019 ◽  
Vol 6 (7) ◽  
pp. 190179 ◽  
Author(s):  
Christine Xue ◽  
Joyce Tran ◽  
Hongsu Wang ◽  
Giovanna Park ◽  
Frederick Hsu ◽  
...  
Keyword(s):  
Growth Rate ◽  
Green Tea ◽  
Epigallocatechin Gallate ◽  
Amyloid Β ◽  
Lag Time ◽  
Aβ Oligomers ◽  
Wide Range ◽  
Aβ Aggregation

Amyloid-β (Aβ) oligomers play a central role in the pathogenesis of Alzheimer's disease. Oligomers of different sizes, morphology and structures have been reported in both in vivo and in vitro studies, but there is a general lack of understanding about where to place these oligomers in the overall process of Aβ aggregation and fibrillization. Here, we show that Aβ42 spontaneously forms oligomers with a wide range of sizes in the same sample. These Aβ42 samples contain predominantly oligomers, and they quickly form fibrils upon incubation at 37°C. When fractionated using ultrafiltration filters, the samples enriched with smaller oligomers form fibrils at a faster rate than the samples enriched with larger oligomers, with both a shorter lag time and faster fibril growth rate. This observation is independent of Aβ42 batches and hexafluoroisopropanol treatment. Furthermore, the fibrils formed by the samples enriched with larger oligomers are more readily solubilized by epigallocatechin gallate, a main catechin component of green tea. These results suggest that the fibrils formed by larger oligomers may adopt a different structure from fibrils formed by smaller oligomers, pointing to a link between oligomer heterogeneity and fibril polymorphism.

scholarly journals The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation

2020 ◽  
Vol 21 (3) ◽  
pp. 1066
Author(s):  
Roberta Corti ◽  
Alysia Cox ◽  
Valeria Cassina ◽  
Luca Nardo ◽  
Domenico Salerno ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Force Microscopy ◽  
Atomic Force ◽  
Nanoparticle Surface ◽  
Afm Imaging ◽  
Aggregation Processes ◽  
Aβ Aggregation ◽  
Aβ Fibrils ◽  
Binding Sequence ◽  
The Brain

The deposition of amyloid-β (Aβ) plaques in the brain is a significant pathological signature of Alzheimer’s disease, correlating with synaptic dysfunction and neurodegeneration. Several compounds, peptides, or drugs have been designed to redirect or stop Aβ aggregation. Among them, the trideca-peptide CWG-LRKLRKRLLR (mApoE), which is derived from the receptor binding sequence of apolipoprotein E, is effectively able to inhibit Aβ aggregation and to promote fibril disaggregation. Taking advantage of Atomic Force Microscopy (AFM) imaging and fluorescence techniques, we investigate if the clustering of mApoE on gold nanoparticles (AuNP) surface may affect its performance in controlling Aβ aggregation/disaggregation processes. The results showed that the ability of free mApoE to destroy preformed Aβ fibrils or to hinder the Aβ aggregation process is preserved after its clustering on AuNP. This allows the possibility to design multifunctional drug delivery systems with clustering of anti-amyloidogenic molecules on any NP surface without affecting their performance in controlling Aβ aggregation processes.

scholarly journals Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates

2017 ◽  
Vol 114 (30) ◽  
pp. 8005-8010 ◽  
Author(s):  
Sean Chia ◽  
Patrick Flagmeier ◽  
Johnny Habchi ◽  
Veronica Lattanzi ◽  
Sara Linse ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Heterogeneous Nucleation ◽  
Amyloid Β ◽  
Catalytic Cycle ◽  
Amyloid Β Peptide ◽  
Complex Interplay ◽  
Parkinson’S Diseases ◽  
Aβ Aggregation ◽  
Aβ Fibrils

The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates. It is thus the specific balance between the concentrations of monomeric and fibrillar α-synuclein that determines the outcome of the Aβ42 aggregation reaction.

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