Kinetic fingerprints differentiate anti-Aβ therapies

Linse, Sara; Scheidt, Tom; Bernfur, Katja; Vendruscolo, Michele; Dobson, Christopher M.; Cohen, Samuel I.; Šileikis, Eimantas; Lundquist, Martin; Qian, Fang; O’Malley, Tiernan T.; Bussière, Thierry; Weinreb, Paul H.; Xu, Catherine K.; Meisl, Georg; Devenish, Sean R. A.; Knowles, Tuomas P. J.; Hansson, Oskar

doi:10.1101/815308

Cited by 21 publications

(24 citation statements)

References 38 publications

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“…The data were analysed by Bayesian inference, according to the following equations. Following correction of fluorescence intensities for plasma autofluorescence, the fraction, f d , of RBD to diffuse into the distal channel is defined by 24 where [R] 0 is the total concentration of RBD, and ρ b and ρ f are the fractions of bound and free RBD to diffuse into the distal channel, respectively. By solving the binding equation, we obtain the following expression for [AbR] where α is the fraction of plasma used in the measurement and [Ab] tot is the total concentration of antibody binding sites in the sample.…”

Section: Methodsmentioning

confidence: 99%

Microfluidic Affinity Profiling reveals a Broad Range of Target Affinities for Anti-SARS-CoV-2 Antibodies in Plasma of COVID-19 Survivors

Schneider

Emmenegger

et al. 2020

Preprint

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The clinical outcome of SARS-CoV-2 infections can range from asymptomatic to lethal, and is thought to be crucially shaped by the quality of the immune response which includes antibody titres and affinity for their targets. Using Microfluidic Antibody Affinity Profiling (MAAP), we determined the aggregate affinities and concentrations of anti-SARS-CoV-2 antibodies in plasma samples of 42 seropositive individuals, 23 of whom were confirmed to be SARS-CoV-2-positive by PCR testing. We found that dissociation constants (Kd) of anti-RBD antibodies spanned more than two orders of magnitude from 80 pM to 25 nM, despite having similar antibody concentrations. Individual patients showed progressively higher antibody concentrations but constant Kd values, suggesting that affinities did not mature over time. 33 sera showed affinities higher than that of the CoV2 spike for its ACE2 receptor. Accordingly, addition of seropositive plasma to pre-formed spike-ACE2 receptor complexes led to their dissociation. Finally, we observed that the RBD of HKU1, OC43, and SARS-CoV coronaviruses, but not unrelated control proteins, were able to compete substantially with the RBD of SARS-CoV-2 in solution. Therefore, the affinity of total plasma immunoglobulins to SARS-CoV-2 is an indicator of the quality of the immune response to SARS-CoV-2, and may help select the most efficacious samples for therapeutic plasmapheresis.

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Section: Methodsmentioning

confidence: 99%

Microfluidic Affinity Profiling reveals a Broad Range of Target Affinities for Anti-SARS-CoV-2 Antibodies in Plasma of COVID-19 Survivors

Schneider

Emmenegger

et al. 2020

Preprint

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“…Increasing evidence suggests that the oligomeric aggregates which form as intermediates during the Aβ deposition process, rather than mature fibrils, are the predominant species capable of inducing neuronal dysfunction [4][5][6][7]. Targeting the rates of formation or the physicochemical properties of Aβ oligomers, therefore, represents one of the most promising therapeutic approaches to the treatment of AD [8,9].…”

Section: Introductionmentioning

confidence: 99%

Rationally Designed Antibodies as Research Tools to Study the Structure–Toxicity Relationship of Amyloid-β Oligomers

Limbocker

Mannini

Cataldi

et al. 2020

IJMS

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Alzheimer’s disease is associated with the aggregation of the amyloid-β peptide (Aβ), resulting in the deposition of amyloid plaques in brain tissue. Recent scrutiny of the mechanisms by which Aβ aggregates induce neuronal dysfunction has highlighted the importance of the Aβ oligomers of this protein fragment. Because of the transient and heterogeneous nature of these oligomers, however, it has been challenging to investigate the detailed mechanisms by which these species exert cytotoxicity. To address this problem, we demonstrate here the use of rationally designed single-domain antibodies (DesAbs) to characterize the structure–toxicity relationship of Aβ oligomers. For this purpose, we use Zn2+-stabilized oligomers of the 40-residue form of Aβ (Aβ40) as models of brain Aβ oligomers and two single-domain antibodies (DesAb18-24 and DesAb34-40), designed to bind to epitopes at residues 18–24 and 34–40 of Aβ40, respectively. We found that the DesAbs induce a change in structure of the Zn2+-stabilized Aβ40 oligomers, generating a simultaneous increase in their size and solvent-exposed hydrophobicity. We then observed that these increments in both the size and hydrophobicity of the oligomers neutralize each other in terms of their effects on cytotoxicity, as predicted by a recently proposed general structure–toxicity relationship, and observed experimentally. These results illustrate the use of the DesAbs as research tools to investigate the biophysical and cytotoxicity properties of Aβ oligomers.

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“…Such data would serve to establish the species and processes associated with an ongoing Aβ42 aggregation reaction that are primarily responsible for causing lipid bilayer permeability. This information would be particularly useful for elucidating the mechanisms of pathological protein aggregation, which still remain poorly understood, a possible reason for the heterogeneous outcome of clinical trials aimed at targeting amyloid formation [22][23][24].…”

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confidence: 99%

Direct measurement of lipid membrane disruption connects kinetics and toxicity of Aβ42 aggregation

Flagmeier

Michaels

et al. 2020

Nat Struct Mol Biol

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The formation of amyloid deposits within human tissues is a defining feature of more than fifty medical disorders, including Alzheimer's disease. Strong genetic and histological evidence links these conditions to the process of protein aggregation, yet it has remained challenging to identify a definitive connection between aggregation and pathogenicity. Using time-resolved fluorescence microscopy of individual synthetic vesicles, we show for the Aβ42 peptide implicated in Alzheimer's disease that the disruption of lipid bilayers correlates linearly with the time course of the levels of transient oligomers generated through secondary nucleation. These findings suggest a specific role of oligomers generated through the catalytic action of fibrillar species during the protein aggregation process, in driving deleterious biological function, and establish a direct causative connection between amyloid formation and its pathological effects. Main text Neurodegenerative conditions including Alzheimer's and Parkinson's diseases [1-5] have

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Kinetic fingerprints differentiate anti-Aβ therapies

Cited by 21 publications

References 38 publications

Microfluidic Affinity Profiling reveals a Broad Range of Target Affinities for Anti-SARS-CoV-2 Antibodies in Plasma of COVID-19 Survivors

Microfluidic Affinity Profiling reveals a Broad Range of Target Affinities for Anti-SARS-CoV-2 Antibodies in Plasma of COVID-19 Survivors

Rationally Designed Antibodies as Research Tools to Study the Structure–Toxicity Relationship of Amyloid-β Oligomers

Direct measurement of lipid membrane disruption connects kinetics and toxicity of Aβ42 aggregation

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