scholarly journals Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment

2002 ◽  
Vol 366 (1) ◽  
pp. 343-351 ◽  
Author(s):  
Lars O. TJERNBERG ◽  
Agneta TJERNBERG ◽  
Niklas BARK ◽  
Yuan SHI ◽  
Bela P. RUZSICSKA ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Structural Features ◽  
Fibril Formation ◽  
Amyloid Β Peptide ◽  
Detailed Model ◽  
Aβ Fibrils ◽  
Β Sheet

The amyloid plaque, consisting of amyloid β-peptide (Aβ) fibrils surrounded by dystrophic neurites, is an invariable feature of Alzheimer's disease. The determination of the molecular structure of Aβ fibrils is a significant goal that may lead to the structure-based design of effective therapeutics for Alzheimer's disease. Technical challenges have thus far rendered this goal impossible. In the present study, we develop an alternative methodology. Rather than determining the structure directly, we design conformationally constrained peptides and demonstrate that only certain ‘bricks’ can aggregate into fibrils morphologically identical to Aβ fibrils. The designed peptides include variants of a decapeptide fragment of Aβ, previously shown to be one of the smallest peptides that (1) includes a pentapeptide sequence necessary for Aβ—Aβ binding and aggregation and (2) can form fibrils indistinguishable from those formed by full-length Aβ. The secondary structure of these bricks is monitored by CD spectroscopy, and electron microscopy is used to study the morphology of the aggregates formed. We then made various residue deletions and substitutions to determine which structural features are essential for fibril formation. From the constraints, statistical analysis of side-chain pair correlations in β-sheets and experimental data, we deduce a detailed model of the peptide strand alignment in fibrils formed by these bricks. Our results show that the constrained decapeptide dimers rapidly form an intramolecular, antiparallel β-sheet and polymerize into amyloid fibrils at low concentrations. We suggest that the formation of an exposed β-sheet (e.g. an Aβ dimer formed by interaction in the decapeptide region) could be a rate-limiting step in fibril formation. A theoretical framework that explains the results is presented in parallel with the data.

scholarly journals Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

2021 ◽  
Vol 118 (4) ◽  
pp. e2023089118 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Kent R. Thurber ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Molecular Conformations ◽  
Layered Architecture ◽  
Fibril Structure ◽  
Aggregation Inhibitors ◽  
Aβ Fibrils ◽  
Β Sheet

Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer’s disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

Inhibition of Aβ(1–40) fibril formation by cyclophilins

2016 ◽  
Vol 473 (10) ◽  
pp. 1355-1368 ◽  
Author(s):  
Marten Villmow ◽  
Monika Baumann ◽  
Miroslav Malesevic ◽  
Rolf Sachs ◽  
Gerd Hause ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Water Soluble ◽  
Main Process ◽  
Amyloid Β Peptide ◽  
Cyclophilin D ◽  
Aβ Amyloid

Cyclophilins interact directly with the Alzheimer's disease peptide Aβ (amyloid β-peptide) and are therefore involved in the early stages of Alzheimer's disease. Aβ binding to CypD (cyclophilin D) induces dysfunction of human mitochondria. We found that both CypD and CypA suppress in vitro fibril formation of Aβ(1–40) at substoichiometric concentrations when present early in the aggregation process. The prototypic inhibitor CsA (cyclosporin A) of both cyclophilins as well as the new water-soluble MM258 derivative prevented this suppression. A SPOT peptide array approach and NMR titration experiments confirmed binding of Aβ(1–40) to the catalytic site of CypD mainly via residues Lys16–Glu22. The peptide Aβ(16–20) representing this section showed submicromolar IC50 values for the peptidyl prolyl cis–trans isomerase activity of CypD and CypA and low-micromolar KD values in ITC experiments. Chemical cross-linking and NMR-detected hydrogen–deuterium exchange experiments revealed a shift in the populations of small Aβ(1–40) oligomers towards the monomeric species, which we investigated in the present study as being the main process of prevention of Aβ fibril formation by cyclophilins.

scholarly journals α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

2019 ◽  
Vol 116 (18) ◽  
pp. 8895-8900 ◽  
Author(s):  
Dylan Shea ◽  
Cheng-Chieh Hsu ◽  
Timothy M. Bi ◽  
Natasha Paranjapye ◽  
Matthew Carter Childers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Secondary Structure ◽  
De Novo ◽  
Specific Binding ◽  
Amyloid Β ◽  
Plaque Burden ◽  
Lag Phase ◽  
Amyloid Β Peptide ◽  
Β Sheet

Alzheimer’s disease (AD) is characterized by the deposition of β-sheet–rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

scholarly journals Stabilization of Neurotoxic Soluble β-Sheet-Rich Conformations of the Alzheimer's Disease Amyloid-β Peptide

2008 ◽  
Vol 94 (7) ◽  
pp. 2752-2766 ◽  
Author(s):  
Deborah J. Tew ◽  
Stephen P. Bottomley ◽  
David P. Smith ◽  
Giuseppe D. Ciccotosto ◽  
Jeffrey Babon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Β Sheet

scholarly journals Destabilization of the Alzheimer’s Amyloid-β Peptide by a Proline-Rich β-Sheet Breaker Peptide: A Molecular Dynamics Simulation Study

2021 ◽  
Author(s):  
Pavan Krishna Kanchi ◽  
Ashok Kumar Dasmahapatra
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Amyloid Β ◽  
Dynamics Simulation ◽  
Amyloid Β Peptide ◽  
Salt Bridges ◽  
Recognition Sequence ◽  
Self Recognition ◽  
Β Sheet

Abstract The amyloid-β peptide exists in the form of fibrils in the plaques found in the brains of patients with Alzheimer’s disease. One of the therapeutic strategies is the design of molecules which can destabilize these fibrils. We present a designed peptide KLVFFP5 with two segments: the self-recognition sequence KLVFF and a β-sheet breaker proline pentamer. Molecular dynamics simulations and docking results showed that this peptide could bind to the protofibrils and destabilize them by establishing hydrophobic contacts and hydrogen bonds with a higher affinity than the KLVFF peptide. In the presence of the KLVFFP5 peptide the β-sheet content of the protofibrils was reduced significantly, the hydrogen bonding network and the salt bridges were disrupted to a greater extent than the KLVFF peptide. Our results indicate that the KLVFFP5 peptide is an effective β-sheet disruptor which can be considered in the therapy of Alzheimer’s disease.

The p3 Peptide, a Naturally Occurring Fragment of the Amyloid-β Peptide (Aβ)Found in Alzheimer's Disease, Has a Greater Aggregation Propensity In Vitro Than Full-Length Aβ, But Does Not Bind Cu2+.

2000 ◽  
Vol 53 (4) ◽  
pp. 321 ◽  
Author(s):  
Feda Ali ◽  
Andrew J. Thompson ◽  
Colin J. Barrow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down's Syndrome ◽  
Amyloid Β ◽  
Down’S Syndrome ◽  
Full Length ◽  
Amyloid Β Peptide ◽  
Sheet Structure ◽  
Β Sheet

Cerebellar preamyloid from both Down’s syndrome and Alzheimer’s disease contains the p3 fragment (Aβ 17–40/42) as a major amyloid-β peptide (Aβ) component. The p3 peptide was previously shown to form amyloid in vitro, but less readily than full-length Aβ. Here we show that the p3 peptide has a greater β-sheet-forming propensity than full-length Aβ. Using circular dichroism spectroscopy we determined that in aqueous solutions the p3 peptide forms β-sheet structure more readily than full-length Aβ. The p3 peptide also has a lower α-helical propensity than full-length Aβ in the structure-forming solvent trifluoroethanol. These results indicate that the lower amyloidogenicity of the p3 peptide is not related to an inability to form β-sheet structure. In this study we also show that, unlike full-length Aβ, the p3 peptide does not bind Cu2+ ions. This inability to bind copper ions may explain why the p3 peptide appears to play a lesser role in Down’s syndrome and Alzheimer’s disease related neurodegeneration than does full-length Aβ.

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

Biomolecules ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 44 ◽  
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.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
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.

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.

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