Cryo‐electron Microscopy Imaging of Alzheimer's Amyloid‐beta 42 Oligomer Displayed on a Functionally and Structurally Relevant Scaffold

Wu, Jinming; Blum, Thorsten B.; Farrell, Daniel P.; DiMaio, Frank; Abrahams, J.P.; Luo, Jinghui

doi:10.1002/anie.202104497

Cited by 48 publications

(61 citation statements)

References 51 publications

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“…In addition, a multitude of currently unknown three-dimensional structures are likely to appear during the aggregation process. Recent research based on cryo-electron microscopy technology has achieved high-resolution structural analysis of Aβ oligomers 115 and tau protein 116 . Therefore, the discovery and clarification of the unknown three-dimensional structure and function of more misfolded proteins will be an essential task.…”

Section: Challenges Of Phage Display Strategies For Ad Applicationsmentioning

confidence: 99%

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Zhang¹,

Zhang²,

Gao³

et al. 2022

Theranostics

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Alzheimer's disease (AD) is an incurable and fatal progressive neurodegenerative disorder associated with memory and cognition impairment. AD is one of the top medical care concerns across the world with a projected economic burden of $2 trillion by 2030. To date, however, there remains no effective disease-modifying therapy available. It is more important than ever to reveal novel therapeutic approaches. Peptide-based biotherapeutics has been a great potential strategy attributed to their distinct and superior biochemical characteristics, such as reproducible chemical synthesis and modification, rapid cell and tissue permeability, and fast blood clearance. Phage display, one of today's most powerful platforms, allows selection and identification of suitable peptide drug candidates with high affinities and specificity toward target, demonstrating the potential to overcome challenges and limitations in AD diagnosis/treatment. We aim to provide the first comprehensive review to summarize the status in this research direction. The biological overview of phage display is described, including basic biology of the phage vectors and construction principle of phage library, biopanning procedure, mirror image phage display, and various binding affinity evaluation approaches. Further, the applications of phage display in AD therapy, targeted drug delivery, and early detection are presented. Finally, we discuss the current challenges and offer a future outlook for further advancing the potential application of phage display on AD and other neurodegenerative diseases.

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Section: Challenges Of Phage Display Strategies For Ad Applicationsmentioning

confidence: 99%

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Zhang¹,

Zhang²,

Gao³

et al. 2022

Theranostics

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show abstract

“…In vivo, the protein aggregates can be detected after staining with a dye or other biomarker. In vitro, the protein aggregates contain regular fibrillar structures that can be visualised by techniques such as electron microscopy (EM) or atomic force microscopy (AFM) [49,50]. It is also possible to characterise the size and charge of the aggregates [51] as well as their aggregation rate, kinetics, formation mechanism and early oligomeric states [52,53].…”

Section: Introductionmentioning

confidence: 99%

“…The main toxic species in many proteinopathies appears not to be the large protein aggregates but rather small soluble intermediate oligomers that form along the aggregation pathways [44,46,48,56]. Being important potential drug targets, these oligomers have been extensively researched, but their sizes, shapes and structures remain unclear [49]. The α-pleated sheet structure might be an important conformational motif of aggregates [57].…”

Section: Introductionmentioning

confidence: 99%

“…The α-pleated sheet structure might be an important conformational motif of aggregates [57]. The oligomers may spread from cell to cell via, e.g., exosomes [48,56], and a possible toxic mechanism for these oligomers is the disruption of cell membranes [49,58]. The formation of oligomers and other protein aggregates can be influenced by a number of factors, including other proteins, small molecules and metal ions [58][59][60][61][62][63].…”

Section: Introductionmentioning

confidence: 99%

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Metals in ALS TDP-43 Pathology

Koski

Ronnevi

Berntsson

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.

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“…In an effort to reveal the molecular basis of α-Syn toxicity and aggregation, the interaction of α-Syn with membranes has been widely explored [9][10][11] . Several models have been presented to explain the α-Syn induced toxicity to lipid membranes: (1) membrane-permeabilizing toroidal or barrel pores 12 ; (2) carpet model of disrupting and thinning membrane 13,14 ; and (3) lipid extraction model 15 . Reciprocally, the nature of the lipid membrane affects the misfolding and aggregation of α-Syn 16 .…”

Section: Introductionmentioning

confidence: 99%

Single-molecule nanopore dielectrophoretic trapping of α-Synuclein with lipid membranes

Yamashita

Hamilton

et al. 2022

Preprint

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The lipid-α-Synuclein (α-Syn) interaction plays a crucial role in the pathogenesis of Parkinson's disease. Here, we trap α-Syn at conjunction of an α-hemolysin (αHL) single nanopore-lipid to investigate the folding and unfolding kinetics of α-Syn in a lipidic environment. The hybridized α-Syn is generated through a reaction between a 5′-thiol-modified nucleotide oligo (dC30) and the α-Syn mutant (A140C). Owing to an applied voltage, single-molecule hybridized α-Syn can be trapped at the single nanopore. The trapping events are associated with dielectrophoretic force. The folding and unfolding events of α-Syn can be observed at the pore-membrane junction through the interpretation of blockade current amplitudes and dwell time. This can be related to the protein quaternary structure influenced by the α-Syn-membrane interaction, allowing further analysis of α-Syn conformational dynamics. We studied how disease-associated metal ions (Cu2+, Zn2+) modulate folding and unfolding of α-Syn at the interface of the membranes and pore, and how α-helical peptidomimetics stabilize the helical conformation of α-Syn in the presence of a membrane. These studies aid our understanding of the complexity of the interaction of α-Syn, lipid membranes, and metal ions, and in using peptidomimetics, a new strategy against α-Syn toxicity and aggregation is advanced.

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Cryo‐electron Microscopy Imaging of Alzheimer's Amyloid‐beta 42 Oligomer Displayed on a Functionally and Structurally Relevant Scaffold

Cited by 48 publications

References 51 publications

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Metals in ALS TDP-43 Pathology

Single-molecule nanopore dielectrophoretic trapping of α-Synuclein with lipid membranes

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