Chirality Dependence of Amyloid β Cellular Uptake and a New Mechanistic Perspective

Dutta, Sonia; Finn, Thomas S.; Kuhn, Ariel J.; Abrams, Benjamin; Raskatov, Jevgenij A.

doi:10.1002/cbic.201800708

Cited by 29 publications

(39 citation statements)

References 31 publications

(11 reference statements)

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“…Recent studies have demonstrated that the uptake of intrinsically disorder proteins, including Aβ, is a key step in its mechanism of toxicity [39][40][41] . It is therefore possible that the trodusquemine-induced displacement of oligomers from cell membranes could also suppress protein uptake and its associated toxicity, as the binding of the oligomers to the membrane is a necessary step for their internalization.…”

Section: Resultsmentioning

confidence: 99%

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

et al. 2020

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The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-β (Aβ) in Alzheimer's disease and α-synuclein (αS) in Parkinson's disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of αS, Aβ and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.

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Section: Resultsmentioning

confidence: 99%

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

et al. 2020

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“…More specifically, the toxicity of aberrant oligomeric protein aggregates has been previously described as a function of size and hydrophobicity for multiple proteins, where the most cytotoxic aggregates are generally small and have extensive hydrophobic surface exposure [ 30 , 32 , 35 ]. These physiochemical properties play a central role in the ability of oligomers to cause cellular dysfunction, which can result from the uptake of the oligomeric proteins into the cell [ 53 , 54 , 55 ], or directly by the oligomer-induced perturbation of cell membranes [ 3 , 36 ]. Here, we utilized rationally designed antibodies (DesAbs) to probe the structure–toxicity relationship of Zn 2+ -stabilized Aβ 40 oligomers, which we adopted as models of the Aβ oligomers that may form in synaptic regions where Zn 2+ tends to be abundant [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

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

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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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“…While monomeric Aβ are considered to be innocuous,7 it can aggregate and adopt a neurotoxic structure(s) 8. It has been shown that extracellular Aβ contributes to the intracellular pool of Aβ and Aβ conformation plays a crucial role in it;9–11 however, there are still significant gaps in our understanding of the mechanisms involved in the formation of neurotoxic Aβ structures.…”

Section: Introductionmentioning

confidence: 99%

Super‐Resolution Infrared Imaging of Polymorphic Amyloid Aggregates Directly in Neurons

et al. 2020

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Loss of memory during Alzheimer's disease (AD), a fatal neurodegenerative disorder, is associated with neuronal loss and the aggregation of amyloid proteins into neurotoxic β‐sheet enriched structures. However, the mechanism of amyloid protein aggregation is still not well understood due to many challenges when studying the endogenous amyloid structures in neurons or in brain tissue. Available methods either require chemical processing of the sample or may affect the amyloid protein structure itself. Therefore, new approaches, which allow studying molecular structures directly in neurons, are urgently needed. A novel approach is tested, based on label‐free optical photothermal infrared super‐resolution microspectroscopy, to study AD‐related amyloid protein aggregation directly in the neuron at sub‐micrometer resolution. Using this approach, amyloid protein aggregates are detected at the subcellular level, along the neurites and strikingly, in dendritic spines, which has not been possible until now. Here, a polymorphic nature of amyloid structures that exist in AD transgenic neurons is reported. Based on the findings of this work, it is suggested that structural polymorphism of amyloid proteins that occur already in neurons may trigger different mechanisms of AD progression.

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Chirality Dependence of Amyloid β Cellular Uptake and a New Mechanistic Perspective

Cited by 29 publications

References 31 publications

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

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

Super‐Resolution Infrared Imaging of Polymorphic Amyloid Aggregates Directly in Neurons

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