Stabilization, Assembly, and Toxicity of Trimers Derived from Aβ

Kreutzer, Adam G.; Yoo, Stan; Spencer, Ryan K.; Nowick, James S.

doi:10.1021/jacs.6b11748

Cited by 64 publications

(97 citation statements)

References 52 publications

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“…We recently demonstrated that stabilizing the trimer formed by peptide 1 through covalent cross-linking allows solution-phase assembly to form higher-order oligomers, such as hexamers and dodecamers. 28 The study presented here demonstrates that hydrophobic interactions between monomers that are not covalently cross-linked can stabilize higher-order oligomers in the same fashion. This finding is significant, because it shows that suitably folded β-hairpin peptides containing amyloidogenic sequences can form stable oligomers.…”

Section: Summary and Conclusionmentioning

confidence: 64%

A Hexamer of a Peptide Derived from Aβ_16–36

et al. 2017

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The absence of high-resolution structures of amyloid oligomers constitutes a major gap in our understanding of amyloid diseases. A growing body of evidence indicates that oligomers of the β-amyloid peptide Aβ are especially important in the progression of Alzheimer’s disease. In many Aβ oligomers, the Aβ monomer components are thought to adopt a β-hairpin conformation. This paper describes the design and study of a macrocyclic β-hairpin peptide derived from Aβ16–36. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis and size exclusion chromatography studies show that the Aβ16–36 β-hairpin peptide assembles in solution to form hexamers, trimers, and dimers. X-ray crystallography reveals that the peptide assembles to form a hexamer in the crystal state and that the hexamer is composed of dimers and trimers. Lactate dehydrogenase release assays show that the oligomers formed by the Aβ16–36 β-hairpin peptide are toxic toward neuronally derived SH-SY5Y cells. Replica-exchange molecular dynamics demonstrates that the hexamer can accommodate full-length Aβ. These findings expand our understanding of the structure, solution-phase behavior, and biological activity of Aβ oligomers and may offer insights into the molecular basis of Alzheimer’s disease.

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Section: Summary and Conclusionmentioning

confidence: 64%

A Hexamer of a Peptide Derived from Aβ_16–36

et al. 2017

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“…Extracellular deposits of Aβ peptides in Alzheimer’s are the main pathological events in AD [ 31 , 32 , 33 , 34 ]. Senile plaques or amyloid plaques mainly consist of small amyloid beta-peptides (Aβ) (up to 42 or 43 amino acids long) [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Ejaz

Wang

Lang

2020

IJMS

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Alzheimer’s disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals’ roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions’ current status in several AD features, and some conflicting reports are present herein.

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“…The deposition of β-amyloid peptide (Aβ) in the brain is one of the pathology hallmarks of AD (Citron, 2010 ; Buendia et al, 2016 ; Sepulcre et al, 2016 ; Kreutzer et al, 2017 ). Although high concentrations of endogenous copper (Cu) (Pal et al, 2015 ; Greenough et al, 2016 ; Xu et al, 2016 ), zinc (Zn) (Kulikova et al, 2015 ; Mezentsev et al, 2016 ), and iron (Fe) (Guo et al, 2015 ; Peters et al, 2015 ; Sands et al, 2016 ; James et al, 2017 ) have been found in these amyloidal plaques, the association of those metal ions with Aβ accumulation has not been well established.…”

Section: Introductionmentioning

confidence: 99%

Serum Copper, Zinc, and Iron Levels in Patients with Alzheimer's Disease: A Meta-Analysis of Case-Control Studies

Zhang

Wang

et al. 2017

Front. Aging Neurosci.

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Background: Many publications have investigated the association between metal ions and the risk of Alzheimer's disease (AD), but the results were ambiguous.Aims: The objective of this study was to assess the association between the serum levels of metals (copper/zinc/iron) and the risk of AD via meta-analysis of case-control studies.Methods: We screened literatures published after 1978 in the Pubmed, Embase, Cochrane library, Web of Science and ClinicalTrials.gov. Electronic databases. By using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the 407 publications, there are 44 of these publications met all inclusion criteria. The Review Manager 5.3 software was used to calculate available data from each study.Results: Consistent with the conclusions of other meta-analysis, our results demonstrated serum copper levels were significantly higher [MD = 9.27, 95% CI (5.02–13.52); p < 0.0001], and the serum zinc levels were significantly lower in AD patients than in healthy controls [MD = −6.12, 95% CI (−9.55, −2.69); p = 0.0005]. Serum iron levels were significantly lower in AD patients than in healthy controls after excluded two studies [MD = −13.01, 95% CI (−20.75, −5.27); p = 0.001].Conclusion: The results of our meta-analysis provided rigorous statistical support for the association of the serum levels of metals and the risk of AD, suggesting a positive relationship between the serum copper levels and AD risk, and a negative relationship between the serum zinc/iron levels and AD risk.

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Stabilization, Assembly, and Toxicity of Trimers Derived from Aβ

Cited by 64 publications

References 52 publications

A Hexamer of a Peptide Derived from Aβ_16–36

A Hexamer of a Peptide Derived from Aβ_16–36

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Serum Copper, Zinc, and Iron Levels in Patients with Alzheimer's Disease: A Meta-Analysis of Case-Control Studies

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Stabilization, Assembly, and Toxicity of Trimers Derived from Aβ

Cited by 64 publications

References 52 publications

A Hexamer of a Peptide Derived from Aβ16–36

A Hexamer of a Peptide Derived from Aβ16–36

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Serum Copper, Zinc, and Iron Levels in Patients with Alzheimer's Disease: A Meta-Analysis of Case-Control Studies

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A Hexamer of a Peptide Derived from Aβ_16–36

A Hexamer of a Peptide Derived from Aβ_16–36