Computational models explain how copper binding to amyloid-β peptide oligomers enhances oxidative pathways

The investigation of the (ZAβ3)2:Aβ complex highlights the energetic contribution of affibody residues to the binding with alzheimer's disease associated Aβ peptides.

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Affinity of Cu+for the Copper-Binding Domain of the Amyloid-β Peptide of Alzheimer’s Disease

Inorganic Chemistry ◽

10.1021/ic100967s ◽

2011 ◽

Vol 50 (5) ◽

pp. 1614-1618 ◽

Cited By ~ 58

Author(s):

Heather A. Feaga ◽

Richard C. Maduka ◽

Monique N. Foster ◽

Veronika A. Szalai

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Binding Domain ◽

Amyloid Β Peptide ◽

Copper Binding

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Mercury and Alzheimer’s Disease: Hg(II) Ions Display Specific Binding to the Amyloid-β Peptide and Hinder Its Fibrillization

Biomolecules ◽

10.3390/biom10010044 ◽

2019 ◽

Vol 10 (1) ◽

pp. 44 ◽

Cited By ~ 9

Author(s):

Cecilia Wallin ◽

Merlin Friedemann ◽

Sabrina B. Sholts ◽

Andra Noormägi ◽

Teodor Svantesson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Metal Ions ◽

Amyloid Fibrils ◽

Specific Binding ◽

Amyloid Β ◽

Binding Mode ◽

Amyloid Β Peptide ◽

Aβ Peptides

Brains and blood of Alzheimer’s disease (AD) patients have shown elevated mercury concentrations, but potential involvement of mercury exposure in AD pathogenesis has not been studied at the molecular level. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. Aβ peptide fibrillization is known to be modulated by metal ions such as Cu(II) and Zn(II). Here, we study in vitro the interactions between Aβ peptides and Hg(II) ions by multiple biophysical techniques. Fluorescence spectroscopy and atomic force microscopy (AFM) show that Hg(II) ions have a concentration-dependent inhibiting effect on Aβ fibrillization: at a 1:1 Aβ·Hg(II) ratio only non-fibrillar Aβ aggregates are formed. NMR spectroscopy shows that Hg(II) ions interact with the N-terminal region of Aβ(1–40) with a micromolar affinity, likely via a binding mode similar to that for Cu(II) and Zn(II) ions, i.e., mainly via the histidine residues His6, His13, and His14. Thus, together with Cu(II), Fe(II), Mn(II), Pb(IV), and Zn(II) ions, Hg(II) belongs to a family of metal ions that display residue-specific binding interactions with Aβ peptides and modulate their aggregation processes.

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Efficient suppression of amyloid-β peptide aggregation and cytotoxicity with photosensitive polymer nanodots

Journal of Materials Chemistry B ◽

10.1039/d0tb00302f ◽

2020 ◽

Vol 8 (26) ◽

pp. 5776-5782 ◽

Cited By ~ 1

Author(s):

Yueling Xu ◽

Lehui Xiao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Peptide Aggregation ◽

Aβ Peptides ◽

Efficient Suppression ◽

Photosensitive Polymer ◽

Aβ Aggregation

The aggregation of amyloid-β (Aβ) peptides is closely related to Alzheimer's disease (AD). These functionalized Pdots manifest effective photo-triggered suppression ability for the Aβ aggregation and cytotoxicity under irradiation.

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A copper-binding site in the cytoplasmic domain of BACE1 identifies a possible link to metal homoeostasis and oxidative stress in Alzheimer's disease

Biochemical Society Transactions ◽

10.1042/bst0350571 ◽

2007 ◽

Vol 35 (3) ◽

pp. 571-573 ◽

Cited By ~ 15

Author(s):

C. Dingwall

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Amyloid Β ◽

Cytoplasmic Domain ◽

Major Constituent ◽

Amyloid Β Peptide ◽

Copper Binding ◽

App Processing ◽

Aβ Amyloid

The amyloidogenic processing pathway of the APP (amyloid precursor protein) generates Aβ (amyloid β-peptide), the major constituent in Alzheimer's disease senile plaques. This processing is catalysed by two unusual membrane-localized aspartic proteinases, β-secretase [BACE1 (β-site APP-cleaving enzyme 1)] and the γ-secretase complex. There is a clear link between APP processing and copper homoeostasis in the brain. APP binds copper and zinc in the extracellular domain and Aβ also binds copper, zinc and iron. We have found that a 24-residue peptide corresponding to the C-terminal domain of BACE1 binds a single copper(I) atom with high affinity through cysteine residues. We also observed that the cytoplasmic domain of BACE1 interacts with CCS, the dedicated copper chaperone for SOD1 (superoxide dismutase 1). Overproduction of BACE1 reduces SOD1 activity in cells. Consequently, SOD1 activity, cytosolic copper and ectodomain cleavage of APP are linked through BACE1.

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Amyloid β-peptide and Alzheimer's disease

Essays in Biochemistry ◽

10.1042/bse0560099 ◽

2014 ◽

Vol 56 ◽

pp. 99-110 ◽

Cited By ~ 15

Author(s):

David Allsop ◽

Jennifer Mayes

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Strong Support ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Amyloid Cascade Hypothesis ◽

Sequence Of Events ◽

Aβ Amyloid ◽

Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

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Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

Current Alzheimer Research ◽

10.2174/1567205015666171227154016 ◽

2018 ◽

Vol 15 (6) ◽

pp. 504-510 ◽

Cited By ~ 9

Author(s):

Sara Sanz-Blasco ◽

Maria Calvo-Rodríguez ◽

Erica Caballero ◽

Monica Garcia-Durillo ◽

Lucia Nunez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Death ◽

Amyloid Β ◽

Epidemiological Data ◽

Amyloid Β Peptide ◽

Aβ Oligomers ◽

Mitochondrial Potential ◽

Disease Modifying Drugs ◽

Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

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