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

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.

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

10.1101/2020.06.28.175885 ◽

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.

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Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting

Nature Communications ◽

10.1038/s41467-021-24900-4 ◽

2021 ◽

Vol 12 (1) ◽

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 kDa, termed AβOs, 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.

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

Biochemical Society Transactions ◽

10.1042/bst0351219 ◽

2007 ◽

Vol 35 (5) ◽

pp. 1219-1223 ◽

Cited By ~ 90

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.

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Structural origin of polymorphism of Alzheimer's amyloid β-fibrils

Biochemical Journal ◽

10.1042/bj20120034 ◽

2012 ◽

Vol 447 (1) ◽

pp. 43-50 ◽

Cited By ~ 20

Author(s):

Audrey Agopian ◽

Zhefeng Guo

Keyword(s):

Amyloid Fibrils ◽

Spin Exchange ◽

Electron Paramagnetic Resonance Spectroscopy ◽

Senile Plaques ◽

Amyloid Β ◽

Side Chain ◽

Resonance Spectroscopy ◽

Amyloid Β Peptide ◽

Amyloid Proteins ◽

Aβ Amyloid

Formation of senile plaques containing amyloid fibrils of Aβ (amyloid β-peptide) is a pathological hallmark of Alzheimer's disease. Unlike globular proteins, which fold into unique structures, the fibrils of Aβ and other amyloid proteins often contain multiple polymorphs. Polymorphism of amyloid fibrils leads to different toxicity in amyloid diseases and may be the basis for prion strains, but the structural origin for fibril polymorphism is still elusive. In the present study we investigate the structural origin of two major fibril polymorphs of Aβ40: an untwisted polymorph formed under agitated conditions and a twisted polymorph formed under quiescent conditions. Using electron paramagnetic resonance spectroscopy, we studied the inter-strand side-chain interactions at 14 spin-labelled positions in the Aβ40 sequence. The results of the present study show that the agitated fibrils have stronger inter-strand spin–spin interactions at most of the residue positions investigated. The two hydrophobic regions at residues 17–20 and 31–36 have the strongest interactions in agitated fibrils. Distance estimates on the basis of the spin exchange frequencies suggest that inter-strand distances at residues 17, 20, 32, 34 and 36 in agitated fibrils are approximately 0.2 Å (1 Å=0.1 nm) closer than in quiescent fibrils. We propose that the strength of inter-strand side-chain interactions determines the degree of β-sheet twist, which then leads to the different association patterns between different cross β-units and thus distinct fibril morphologies. Therefore the inter-strand side-chain interaction may be a structural origin for fibril polymorphism in Aβ and other amyloid proteins.

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Effect of Membrane Cholesterol on the Structure of Alzheimer's Amyloid β Peptide in Lipid Bilayers

Biophysical Journal ◽

10.1016/j.bpj.2012.11.1348 ◽

2013 ◽

Vol 104 (2) ◽

pp. 239a

Author(s):

Jason O. Matos ◽

Jeffrey Bulson ◽

Suren A. Tatulian

Keyword(s):

Lipid Bilayers ◽

Amyloid Β ◽

Membrane Cholesterol ◽

Amyloid Β Peptide

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Monomeric amyloid β-peptide (1-42) significantly populates compact fibril-like conformations

10.1101/2020.06.23.156620 ◽

2020 ◽

Author(s):

Bogdan Barz ◽

Alexander K. Buell ◽

Soumav Nath

Keyword(s):

Amyloid Fibrils ◽

Amyloid Β ◽

Random Coil ◽

Amyloid Β Peptide ◽

Secondary Nucleation ◽

Fibril Structure ◽

Amyloid Fibril Formation ◽

Dynamics Simulations ◽

The Individual ◽

Structural Ensemble

AbstractThe aggregation of the amyloid β (Aβ) peptide is a major hallmark of Alzheimer’s disease. This peptide can aggregate into oligomers, proto-fibrils, and mature fibrils, which eventually assemble into amyloid plaques. The peptide monomers are the smallest assembly units, and play an important role in most of the individual processes involved in amyloid fibril formation, such as primary and secondary nucleation and elongation. The structure of the Aβ monomer has been shown to be very dynamic and mostly disordered, both in experimental and in computational studies, similar to a random coil. This structural state of the monomer contrasts with the very stable and well defined structural core of the amyloid fibrils. An important question is whether the monomer can adopt transient fibril-like conformations in solution and what role such conformations might play in the aggregation process. Here we use enhanced and extensive molecular dynamics simulations to study the Aβ42 monomer structural flexibility with different force fields, water models and salt concentrations. We show that the monomer behaves as a random coil under different simulation conditions. Importantly, we find a conformation with the N-terminal region structured very similarly to that of recent experimentally determined fibril models. This is to the best of our knowledge the first monomeric structural ensemble to show such a similarity with the fibril structure.

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6-gingerol interferes with amyloid-beta (Aβ) peptide aggregation

10.1101/2021.01.03.425159 ◽

2021 ◽

Author(s):

Elina Berntsson ◽

Suman Paul ◽

Sabrina B. Sholts ◽

Jüri Jarvet ◽

Andreas Barth ◽

...

Keyword(s):

Animal Studies ◽

Amyloid Fibrils ◽

Amyloid Β ◽

Nutritional Supplement ◽

Aβ Oligomers ◽

Microscopy Imaging ◽

Positive Effects ◽

Age Related ◽

Soluble Aβ Oligomers

AbstractAlzheimer’s disease (AD) is the most prevalent age-related cause of dementia. AD affects millions of people worldwide, and to date there is no cure. The pathological hallmark of AD brains is deposition of amyloid plaques, which mainly consist of amyloid-β (Aβ) peptides, commonly 40 or 42 residues long, that have aggregated into amyloid fibrils. Intermediate aggregates in the form of soluble Aβ oligomers appear to be highly neurotoxic. Cell and animal studies have previously demonstrated positive effects of the molecule 6-gingerol on AD pathology. Gingerols are the main active constituents of the ginger root, which in many cultures is a traditional nutritional supplement for memory enhancement. Here, we use biophysical experiments to characterize in vitro interactions between 6-gingerol and Aβ40 peptides. Our experiments with atomic force microscopy imaging, and nuclear magnetic resonance and Thioflavin-T fluorescence spectroscopy, show that the hydrophobic 6-gingerol molecule interferes with formation of Aβ40 aggregates, but does not interact with Aβ40 monomers. Thus, together with its favourable toxicity profile, 6-gingerol appears to display many of the desired properties of an anti-AD compound.

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

Physical Chemistry Chemical Physics ◽

10.1039/c6cp01014h ◽

2016 ◽

Vol 18 (18) ◽

pp. 12582-12591 ◽

Cited By ~ 37

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.

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