Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation

Braun, Gabriel A.; Dear, Alexander J.; Sanagavarapu, Kalyani; Zetterberg, Henrik; Linse, Sara

doi:10.1039/d1sc02990h

Cited by 22 publications

(35 citation statements)

References 71 publications

(122 reference statements)

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“…Depending on the goal of the project however, this specificity of quantified species may also be a limitation of these technologies. Unlike mass-spectrometry, which can be used to flexibly identify and quantify post-translational modifications such as phosphorylation, and the presence of novel protease-cleaved fragments, such as C-terminal TDP-43 ( 27 ), or specific processed peptides such as those from amyloid-β ( 28 ) or VGF ( 29 ), antibody pair technology does not have this flexibility.…”

Section: Discussionmentioning

confidence: 99%

Technical Performance Evaluation of Olink Proximity Extension Assay for Blood-Based Biomarker Discovery in Longitudinal Studies of Alzheimer's Disease

et al. 2022

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The core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers; amyloid-β (Aß), total tau (t-tau), and phosphorylated tau (p-tau181), are strong indicators of the presence of AD pathology, but do not correlate well with disease progression, and can be difficult to implement in longitudinal studies where repeat biofluid sampling is required. As a result, blood-based biomarkers are increasingly being sought as alternatives. In this study, we aimed to evaluate a promising blood biomarker discovery technology, Olink Proximity Extension Assays for technical reproducibility characteristics in order to highlight the advantages and disadvantages of using this technology in biomarker discovery in AD. We evaluated the performance of five Olink Proteomic multiplex proximity extension assays (PEA) in plasma samples. Three technical control samples included on each plate allowed calculation of technical variability. Biotemporal stability was measured in three sequential annual samples from 54 individuals with and without AD. Coefficients of variation (CVs), analysis of variance (ANOVA), and variance component analyses were used to quantify technical and individual variation over time. We show that overall, Olink assays are technically robust, with the largest experimental variation stemming from biological differences between individuals for most analytes. As a powerful illustration of one of the potential pitfalls of using a multi-plexed technology for discovery, we performed power calculations using the baseline samples to demonstrate the size of study required to overcome the need for multiple test correction with this technology. We show that the power of moderate effect size proteins was strongly reduced, and as a result investigators should strongly consider pooling resources to perform larger studies using this multiplexed technique where possible.

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Section: Discussionmentioning

confidence: 99%

Technical Performance Evaluation of Olink Proximity Extension Assay for Blood-Based Biomarker Discovery in Longitudinal Studies of Alzheimer's Disease

et al. 2022

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“…Fibrillogenesis is strictly related to the aggregation of Aβ 1-42 and Aβ 1-40. A recent study has demonstrated the effect of the combinations of monomers Aβ37, Aβ38 and Aβ 1-40 on the growth of Aβ fibrils [ 38 ]. The study revealed that smaller isoforms of Aβ (37 or 38) can aggregate by themselves and with longer forms.…”

Section: Molecular Neuropathology Of Alzheimer’s Disease and Related ...mentioning

confidence: 99%

“…The study revealed that smaller isoforms of Aβ (37 or 38) can aggregate by themselves and with longer forms. Aβ37 and Aβ38 take a longer time to transform into fibrils than Aβ 1-42 and Aβ 1-40, which transform by an autocatalytic secondary nucleation reaction [ 38 ]. Aβ 1-42 isoforms aggregate more rapidly than other isoforms, taking less than an hour, while shorter forms take several days to transform [ 38 ].…”

Section: Molecular Neuropathology Of Alzheimer’s Disease and Related ...mentioning

confidence: 99%

“…Aβ37 and Aβ38 take a longer time to transform into fibrils than Aβ 1-42 and Aβ 1-40, which transform by an autocatalytic secondary nucleation reaction [ 38 ]. Aβ 1-42 isoforms aggregate more rapidly than other isoforms, taking less than an hour, while shorter forms take several days to transform [ 38 ]. Smaller and more slowly fibrillating forms of Aβ have an inhibitory effect on the rate of senile plaque formation [ 38 ].…”

Section: Molecular Neuropathology Of Alzheimer’s Disease and Related ...mentioning

confidence: 99%

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Biomarkers for the Diagnosis of Alzheimer’s Disease in Clinical Practice: The Role of CSF Biomarkers during the Evolution of Diagnostic Criteria

Dulewicz

Kulczyńska-Przybik

Mroczko

et al. 2022

IJMS

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Alzheimer’s disease (AD) is a progressive condition and the most common cause of dementia worldwide. The neuropathological changes characteristic of the disorder can be successfully detected before the development of full-blown AD. Early diagnosis of the disease constitutes a formidable challenge for clinicians. CSF biomarkers are the in vivo evidence of neuropathological changes developing in the brain of dementia patients. Therefore, measurement of their concentrations allows for improved accuracy of clinical diagnosis. Moreover, AD biomarkers may provide an indication of disease stage. Importantly, the CSF biomarkers of AD play a pivotal role in the new diagnostic criteria for the disease, and in the recent biological definition of AD by the National Institute on Aging, NIH and Alzheimer’s Association. Due to the necessity of collecting CSF by lumbar puncture, the procedure seems to be an important issue not only from a medical, but also a legal, viewpoint. Furthermore, recent technological advances may contribute to the automation of AD biomarkers measurement and may result in the establishment of unified cut-off values and reference limits. Moreover, a group of international experts in the field of AD biomarkers have developed a consensus and guidelines on the interpretation of CSF biomarkers in the context of AD diagnosis. Thus, technological advancement and expert recommendations may contribute to a more widespread use of these diagnostic tests in clinical practice to support a diagnosis of mild cognitive impairment (MCI) or dementia due to AD. This review article presents up-to-date data regarding the usefulness of CSF biomarkers in routine clinical practice and in biomarkers research.

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“…Interactions between A alloforms could modulate their aggregation behaviors in vitro. 70 Previous studies suggeste d that there is a significant molecular cross -talk between A40 monomers and various aggregation states of A 42. 40,42,44 In particular, A40 monomers have strong binding affinity for A 42 aggregates.…”

Section: Seeding and Self-aggregating Effects Of Rmco520amentioning

confidence: 99%

Site Specific NMR Characterization of Abeta-40 Oligomers Cross Seeded by Abeta-42 Oligomers

Chang

et al. 2022

Preprint

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Extracellular accumulation of β amyloid peptides of 40 (Aβ40) and 42 residues (Aβ42) has been considered as one of the hallmarks in the pathology of Alzheimer’s disease. In this work, we are able to prepare oligomeric aggregates of Aβ with uniform size and high structural homogeneity. Our experimental design is to incubate Aβ peptides in reverse micelles (RMs) so that the peptides could aggregate only through a single nucleation process and the size of the oligomers is confined by the physical dimension of the reverse micelles. The hence obtained Aβ oligomers (AβOs) are 23 nm in diameter and they belong to the category of high molecular-weight (MW) oligomers. The solid-state NMR data revealed that Aβ40Os adopt the structural motif of β-loop-β but the chemical shifts manifested that they are structurally different from low-MW AβOs and mature fibrils. From the thioflavin-T results, we found that high-MW Aβ42Os can seed the fibrillization of Aβ40 monomers. Our protocol allows performing cross-seeding experiments among oligomeric species. By comparing the chemical shifts of Aβ40Os cross seeded by Aβ42Os and those of Aβ40Os prepared in the absence of Aβ42Os, we observed that the structures of E11, K16, and E22 were altered, whereas the backbone conformation of the β-sheet region near the C-terminus is structurally invariant. The use of reverse micelles allows hitherto the most detailed characterization of the structural variability of Aβ40Os.

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Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation

Abstract: The pathology of Alzheimer’s disease is connected to the aggregation of β-amyloid (Aβ) peptide, which in vivo exists as a number of length-variants. Truncations and extensions are found at both...

Cited by 22 publications

References 71 publications

Technical Performance Evaluation of Olink Proximity Extension Assay for Blood-Based Biomarker Discovery in Longitudinal Studies of Alzheimer's Disease

Technical Performance Evaluation of Olink Proximity Extension Assay for Blood-Based Biomarker Discovery in Longitudinal Studies of Alzheimer's Disease

Biomarkers for the Diagnosis of Alzheimer’s Disease in Clinical Practice: The Role of CSF Biomarkers during the Evolution of Diagnostic Criteria

Site Specific NMR Characterization of Abeta-40 Oligomers Cross Seeded by Abeta-42 Oligomers

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