Rational design of a conformation-specific antibody for the quantification of A beta oligomers

The accurate quantification of the amounts of small oligomeric assemblies formed by the amyloid β (Aβ) peptide represents a major challenge in the Alzheimer’s field. There is therefore great interest in the development of methods to specifically detect these oligomers by distinguishing them from larger aggregates. The availability of these methods will enable the development of effective diagnostic and therapeutic interventions for this and other diseases related to protein misfolding and aggregation. We describe here a single-domain antibody able to selectively quantify oligomers of the Aβ peptide in isolation and in complex protein mixtures from animal models of disease

Rational design of a conformation-specific antibody for the quantification of Aβ oligomers.

Protein misfolding and aggregation is the hallmark of numerous human disorders, including Alzheimer's disease. This process involves the formation of transient and heterogeneous soluble oligomers, some of which are highly cytotoxic. A major challenge for the development of effective diagnostic and therapeutic tools is thus the detection and quantification of these elusive oligomers. Here, to address this problem, we develop a two-step rational design method for the discovery of oligomer-specific antibodies. The first step consists of an "antigen scanning" phase in which an initial panel of antibodies is designed to bind different epitopes covering the entire sequence of a target protein. This procedure enables the determination through in vitro assays of the regions exposed in the oligomers but not in the fibrillar deposits. The second step involves an "epitope mining" phase, in which a second panel of antibodies is designed to specifically target the regions identified during the scanning step. We illustrate this method in the case of the amyloid β (Aβ) peptide, whose oligomers are associated with Alzheimer's disease. Our results show that this approach enables the accurate detection and quantification of Aβ oligomers in vitro, and in Caenorhabditis elegans and mouse hippocampal tissues

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

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

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

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

Rationally designed antibodies as research tools to study the structure–toxicity relationship of amyloid-β oligomers

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

Dutch Norms for the Eyberg Child Behavior Inventory: Comparisons with other Western Countries

The Eyberg Child Behavior Inventory (ECBI) is one of the most widely used and well-validated parent rating scales for children’s disruptive behavior. This screening instrument is a short, targetted and easy to implement inventory with good psychometric properties and is normed for different countries, among which the United States, Spain, Sweden and Norway. The ECBI has been successfully used for research and clinical purposes, in several countries including The Netherlands. To date, Dutch studies have relied on Scandinavian or US norm scores. However, this may be problematic because of cross-cultural differences in the degree to which certain behaviors are seen as problematic by parents. The main goal of this paper therefore was to obtain norm scores for The Netherlands among 6462 Dutch children aged 4 to 8 years (M age = 6.37 years; SD = 1.32; 50.6% boys). In line with previous research, we found small differences on the mean sum scores across children of different ages (intensity scale) and gender (intensity and problem scale). Therefore, Dutch norm scores were provided age- and gender specific. Our results showed that disruptive behavior of children in the most rural areas was reported as occurring less frequently and was seen as less problematic by parents compared to the disruptive behavior of children in less rural areas. Finally, we found that Dutch norm scores on the ECBI were significantly lower than US norm scores, and significantly higher on the intensity scale (but not the problem scale) than Norwegian and Swedish norm scores

Vantage sensitivity: a framework for individual differences in response to psychological intervention

Purpose People differ significantly in their response to psychological intervention, with some benefitting more from treatment than others. According to the recently proposed theoretical framework of vantage sensitivity, some of this variability may be due to individual differences in environmental sensitivity, the inherent ability to register, and process external stimuli. In this paper, we apply the vantage sensitivity framework to the field of psychiatry and clinical psychology, proposing that some people are more responsive to the positive effects of psychological intervention due to heightened sensitivity. Methods After presenting theoretical frameworks related to environmental sensitivity, we review a selection of recent studies reporting individual differences in the positive response to psychological intervention. Results A growing number of studies report that some people benefit more from psychological intervention than others as a function of genetic, physiological, and psychological characteristics. These studies support the vantage sensitivity proposition that treatment response is influenced by factors associated with heightened sensitivity to environmental influences. More recently, studies have also shown that sensitivity can be measured with a short questionnaire which appears to predict the response to psychological intervention. Conclusions Vantage sensitivity is a framework with significant relevance for our understanding of widely observed heterogeneity in treatment response. It suggests that variability in response to treatment is partly influenced by people’s differing capacity for environmental sensitivity, which can be measured with a short questionnaire. Application of the vantage sensitivity framework to psychiatry and clinical psychology may improve our knowledge regarding when, how, and for whom interventions work