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

ABSTRACT: Alzheimer's disease is associated with the aggregation of the amyloid-? peptide (A?), resulting in the deposition of amyloid plaques in brain tissue. Recent scrutiny of the mechanisms by which A? aggregates induce neuronal dysfunction has highlighted the importance of the A? 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 A? oligomers. For this purpose, we use Zn2+-stabilized oligomers of the 40-residue form of A? (A?40) as models of brain A? oligomers and two single-domain antibodies (DesAb18-24 and DesAb34-40), designed to bind to epitopes at residues 18-24 and 34-40 of A?40, respectively. We found that the DesAbs induce a change in structure of the Zn2+-stabilized A?40 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 A? oligomers.

SUBMITTER: Limbocker R

PROVIDER: S-EPMC7352524 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Limbocker Ryan R Mannini Benedetta B Cataldi Rodrigo R Chhangur Shianne S Wright Aidan K AK Kreiser Ryan P RP Albright J Alex JA Chia Sean S Habchi Johnny J Sormanni Pietro P Kumita Janet R JR Ruggeri Francesco S FS Dobson Christopher M CM Chiti Fabrizio F Aprile Francesco A FA Vendruscolo Michele M

International journal of molecular sciences 20200625 12

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 ...[more]

PMID: 32630615

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Project description:Recent evidence suggests that high molecular weight soluble oligomeric Abeta (oAbeta) assemblies (also known as Abeta-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in Alzheimer disease (AD). To date, most in vivo studies of oAbeta/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD or from the conditioned media of Abeta-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oAbeta/ADDLs generated in situ from the physiological processing of human amyloid precursor protein (APP) and presenitin1 (PS1) transgenes.We produced and histologically characterized single transgenic mice overexpressing APP(E693Q) or APP(E693Q) X PS1DeltaE9 bigenic mice. APP(E693Q) mice were studied in the Morris water maze (MWM) task at 6 and 12 months of age. Following the second MWM evaluation, mice were sacrificed, and brains were assayed for Abetatotal, Abeta40, Abeta42, and oAbeta/ADDLs by enzyme-linked immunosorbent assay (ELISA) and were also histologically examined. Based on results from the oAbeta/ADDL ELISA, we assigned individual APP(E693Q) mice to either an undetectable oAbeta/ADDLs group or a readily detectable oAbeta/ADDLs group. A days to criterion (DTC) analysis was used to determine delays in acquisition of the MWM task.Both single transgenic and bigenic mice developed intraneuronal accumulation of APP/Abeta, although only APP(E693Q) X PS1Delta9 bigenic mice developed amyloid plaques. The APP(E693Q) mice did not develop amyloid plaques at any age studied, up to 30 months. APP(E693Q) mice were tested for spatial learning and memory, and only 12-month-old APP(E693Q) mice with readily detectable oAbeta/ADDLs displayed a significant delay in acquisition of the MWM task when compared to nontransgenic littermates.These data suggest that cerebral oAbeta/ADDL assemblies generated in brain in situ from human APP transgenes may be associated with cognitive impairment. We propose that a DTC analysis may be a sensitive method for assessing the cognitive impact in mice of endogenously generated oligomeric human Abeta assemblies. ANN NEUROL 2010.

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

Publications

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

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