Stabilizing amyloid-β peptide by the N-terminus capture is capable of preventing and eliminating amyloid-β oligomers

2017 ◽  
Vol 53 (54) ◽  
pp. 7673-7676 ◽  
Author(s):  
Gesi Wen ◽  
Daoyuan Chen ◽  
Wenjing Qin ◽  
Binhua Zhou ◽  
Youqiao Wang ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
N Terminus ◽  
Novel Strategy

A novel strategy to prevent and eliminate amyloid-β (Aβ) oligomers from either the early aggregation or the fibril dissolution pathway is described.

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

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
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.

scholarly journals Endo-lysosomal Aβ concentration and pH enable formation of Aβ oligomers that potently induce Tau missorting

2020 ◽  
Author(s):  
Marie P. Schützmann ◽  
Filip Hasecke ◽  
Sarah Bachmann ◽  
Mara Zielinski ◽  
Sebastian Hänsch ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
Aβ Oligomers ◽  
Lysosomal Ph ◽  
Amyloid Fibril Formation ◽  
Aβ Amyloid ◽  
Key Factor ◽  
Lysosomal System

AbstractAmyloid-β peptide (Aβ) forms metastable oligomers >50 kD, termed AβOs or protofibrils, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of the dimeric Aβ variant dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs.

Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction

2007 ◽  
Vol 35 (5) ◽  
pp. 1219-1223 ◽  
Author(s):  
M.J. Rowan ◽  
I. Klyubin ◽  
Q. Wang ◽  
N.W. Hu ◽  
R. Anwyl
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Nitrosative Stress ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Aβ Amyloid

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Aβ (amyloid β-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Aβ oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Aβ, the αv integrin extracellular cell matrix-binding protein and the cytokine TNFα (tumour necrosis factor α) type-1 death receptor mediate Aβ oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFα or genetic knockout of TNF-R1s (type-1 TNFα receptors) prevented Aβ-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to αv-containing integrins abrogated LTP block by Aβ. Protection against the synaptic plasticity-disruptive effects of soluble Aβ was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Aβ oligomers in preclinical AD.

The inhibitory mechanism of a fullerene derivative against amyloid-β peptide aggregation: an atomistic simulation study

2016 ◽  
Vol 18 (18) ◽  
pp. 12582-12591 ◽  
Author(s):  
Yunxiang Sun ◽  
Zhenyu Qian ◽  
Guanghong Wei
Keyword(s):  
Simulation Study ◽  
Atomistic Simulation ◽  
Amyloid Β ◽  
Fullerene Derivative ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Inhibitory Mechanism ◽  
Aβ Oligomers ◽  
Β Sheets

Fullerene inhibits the formation of inter-peptide β-sheets and β-hairpin motifs of toxic Aβ oligomers by binding to F4, Y10, L17–A21 and I31–V40 residues.

scholarly journals Generation of the Amyloid-β Peptide N Terminus inSaccharomyces cerevisiaeExpressing Human Alzheimer's Amyloid-β Precursor Protein

1999 ◽  
Vol 274 (48) ◽  
pp. 33843-33846 ◽  
Author(s):  
Jeffrey P. Greenfield ◽  
Huaxi Xu ◽  
Paul Greengard ◽  
Sam Gandy ◽  
Mary Seeger
Keyword(s):  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
N Terminus

scholarly journals Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments

2016 ◽  
Vol 113 (39) ◽  
pp. 10866-10871 ◽  
Author(s):  
Montserrat Serra-Batiste ◽  
Martí Ninot-Pedrosa ◽  
Mariam Bayoumi ◽  
Margarida Gairí ◽  
Giovanni Maglia ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Lipid Bilayers ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Cellular Membrane ◽  
Specific Structure ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Detergent Micelle ◽  
Detergent Micelles

The formation of amyloid-β peptide (Aβ) oligomers at the cellular membrane is considered to be a crucial process underlying neurotoxicity in Alzheimer’s disease (AD). Therefore, it is critical to characterize the oligomers that form within a membrane environment. To contribute to this characterization, we have applied strategies widely used to examine the structure of membrane proteins to study the two major Aβ variants, Aβ40 and Aβ42. Accordingly, various types of detergent micelles were extensively screened to identify one that preserved the properties of Aβ in lipid environments—namely the formation of oligomers that function as pores. Remarkably, under the optimized detergent micelle conditions, Aβ40 and Aβ42 showed different behavior. Aβ40 aggregated into amyloid fibrils, whereas Aβ42 assembled into oligomers that inserted into lipid bilayers as well-defined pores and adopted a specific structure with characteristics of a β-barrel arrangement that we named β-barrel pore-forming Aβ42 oligomers (βPFOsAβ42). Because Aβ42, relative to Aβ40, has a more prominent role in AD, the higher propensity of Aβ42 to form βPFOs constitutes an indication of their relevance in AD. Moreover, because βPFOsAβ42 adopt a specific structure, this property offers an unprecedented opportunity for testing a hypothesis regarding the involvement of βPFOs and, more generally, membrane-associated Aβ oligomers in AD.

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

2020 ◽  
Vol 21 (12) ◽  
pp. 4542 ◽  
Author(s):  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Rodrigo Cataldi ◽  
Shianne Chhangur ◽  
Aidan K. Wright ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Single Domain ◽  
Simultaneous Increase ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Single Domain Antibodies ◽  
Structure Toxicity Relationship ◽  
Relationship Of ◽  
Toxicity Relationship ◽  
Research Tools

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.

The role of amyloid β in the pathogenesis of Alzheimer's disease

2013 ◽  
Vol 66 (5) ◽  
pp. 362-366 ◽  
Author(s):  
Barnabas James Gilbert
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Experimental Models ◽  
Integrated System ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Toxic Agent ◽  
Aβ Oligomer

The amyloid-β peptide (Aβ) is widely considered to be the major toxic agent in the pathogenesis of Alzheimer's disease, a condition which afflicts approximately 36 million people worldwide. Despite a plethora of studies stretching back over two decades, identifying the toxic Aβ species has proved difficult. Debate has centred on the Aβ fibril and oligomer. Despite support from numerous experimental models, important questions linger regarding the role of the Aβ oligomer in particular. It is likely a huge array of oligomers, rather than a single species, which cause toxicity. Reappraisal of the role of the Aβ fibril points towards a dynamic relationship with the Aβ oligomer within an integrated system, as supported by evidence from microglia. However, some continue to doubt the pathological role of amyloid β, instead proposing a protective role. If the field is to progress, all Aβ oligomers should be characterised, the nomenclature revised and a consistent experimental protocol defined. For this to occur, collaboration will be required between major research groups and innovative analytical tools developed. Such action must surely be taken if amyloid-based therapeutic endeavour is to progress.

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