An ultra‐sensitive immunoassay detects and quantifies soluble Aβ oligomers in human plasma

2021 ◽  
Author(s):  
Lei Liu ◽  
Hyunchang Kwak ◽  
Trebor L. Lawton ◽  
Shan‐Xue Jin ◽  
Angela L. Meunier ◽  
...  
Keyword(s):  
Human Plasma ◽  
Aβ Oligomers ◽  
Soluble Aβ Oligomers

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 Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression

2021 ◽  
Vol 22 (12) ◽  
pp. 6355
Author(s):  
Martin Tolar ◽  
John Hey ◽  
Aidan Power ◽  
Susan Abushakra
Keyword(s):  
Disease Progression ◽  
Late Stage ◽  
Large Body ◽  
Amyloid Plaque ◽  
Distinct Species ◽  
Clinical Effects ◽  
Aβ Oligomers ◽  
Amyloid Toxicity ◽  
Sequence Of Events ◽  
Soluble Aβ Oligomers

A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.

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.

The case for soluble Aβ oligomers as a drug target in Alzheimer's disease

2013 ◽  
Vol 34 (5) ◽  
pp. 261-266 ◽  
Author(s):  
Franz Hefti ◽  
William F. Goure ◽  
Jasna Jerecic ◽  
Kent S. Iverson ◽  
Patricia A. Walicke ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Target ◽  
Aβ Oligomers ◽  
Soluble Aβ Oligomers

scholarly journals 6-gingerol interferes with amyloid-beta (Aβ) peptide aggregation

2021 ◽  
Author(s):  
Elina Berntsson ◽  
Suman Paul ◽  
Sabrina B. Sholts ◽  
Jüri Jarvet ◽  
Andreas Barth ◽  
...  
Keyword(s):  
Animal Studies ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Nutritional Supplement ◽  
Aβ Oligomers ◽  
Microscopy Imaging ◽  
Positive Effects ◽  
Age Related ◽  
Soluble Aβ Oligomers

AbstractAlzheimer’s disease (AD) is the most prevalent age-related cause of dementia. AD affects millions of people worldwide, and to date there is no cure. The pathological hallmark of AD brains is deposition of amyloid plaques, which mainly consist of amyloid-β (Aβ) peptides, commonly 40 or 42 residues long, that have aggregated into amyloid fibrils. Intermediate aggregates in the form of soluble Aβ oligomers appear to be highly neurotoxic. Cell and animal studies have previously demonstrated positive effects of the molecule 6-gingerol on AD pathology. Gingerols are the main active constituents of the ginger root, which in many cultures is a traditional nutritional supplement for memory enhancement. Here, we use biophysical experiments to characterize in vitro interactions between 6-gingerol and Aβ40 peptides. Our experiments with atomic force microscopy imaging, and nuclear magnetic resonance and Thioflavin-T fluorescence spectroscopy, show that the hydrophobic 6-gingerol molecule interferes with formation of Aβ40 aggregates, but does not interact with Aβ40 monomers. Thus, together with its favourable toxicity profile, 6-gingerol appears to display many of the desired properties of an anti-AD compound.

scholarly journals Soluble Aβ Oligomers Impair Dipolar Heterodendritic Plasticity by Activation of mGluR in the Hippocampal CA1 Region

iScience ◽  
2018 ◽  
Vol 6 ◽  
pp. 138-150 ◽  
Author(s):  
Jianhua Zhao ◽  
Anna Li ◽  
Molly Rajsombath ◽  
Yifan Dang ◽  
Dennis J. Selkoe ◽  
...  
Keyword(s):  
Aβ Oligomers ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1 ◽  
Soluble Aβ Oligomers

scholarly journals Soluble Aβ oligomers and protofibrils induce NLRP3 inflammasome activation in microglia

2020 ◽  
Vol 155 (6) ◽  
pp. 650-661 ◽  
Author(s):  
Asta Lučiūnaitė ◽  
Róisín M. McManus ◽  
Marija Jankunec ◽  
Ildikó Rácz ◽  
Cira Dansokho ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Aβ Oligomers ◽  
Nlrp3 Inflammasome Activation ◽  
Soluble Aβ Oligomers
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