Imaging Amyloid-β Membrane Interactions: Ion-Channel Pores and Lipid-Bilayer Permeability in Alzheimer's Disease.

The accumulation of the amyloid-β peptides (Aβ) is central to the development of Alzheimer's disease. The mechanism by which Aβ triggers a cascade of events that leads to dementia is a topic of intense investigation. Aβ self-associates into a series of complex assemblies with different structural and biophysical properties.

Copper(II) Can Kinetically Trap Arctic and Italian Amyloid-β as Toxic Oligomers, Mimicking Cu(II) Binding to Wild-Type Amyloid-β: Implications for Familial Alzheimer's Disease.

The self-association of amyloid-β (Aβ) peptide into neurotoxic oligomers is believed to be central to Alzheimer's disease (AD). Copper is known to impact Aβ assembly, while disrupted copper homeostasis impacts phenotype in Alzheimer's models. Here we show the presence of substoichiometric Cu(II) has very different impacts on the assembly of Aβ40 and Aβ42 isoforms.

Impact of Membrane Phospholipids and Exosomes on the Kinetics of Amyloid-β Fibril Assembly.

Alzheimer's disease (AD) is linked with the self-association of the amyloid-β peptide (Aβ) into oligomers and fibrils. The brain is a lipid rich environment for Aβ to assemble, while the brain membrane composition varies in an age dependent manner, we have therefore monitored the influence of lipid bilayer composition on the kinetics of Aβ40 fibril assembly. Using global-fitting models of fibril formation kinetics, we show that the microscopic rate constant for primary nucleation is influenced by variations in phospholipid composition.

Imaging Amyloid-β Membrane Interactions: Ion-Channel Pores and Lipid-Bilayer Permeability in Alzheimer's Disease.

The accumulation of the amyloid-β peptides (Aβ) is central to the development of Alzheimer's disease. The mechanism by which Aβ triggers a cascade of events that leads to dementia is a topic of intense investigation. Aβ self-associates into a series of complex assemblies with different structural and biophysical properties.

pH Dependence of Amyloid-β Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes.

Central to Alzheimer's disease (AD) is the assembly of the amyloid-beta peptide (Aβ) into fibrils. A reduction in pH accompanying inflammation or subcellular compartments, may accelerate fibril formation as the pH approaches Aβ's isoelectric point (pI). Using global fitting of fibril formation kinetics over a range of pHs, we identify the impact net charge has on individual fibril assembly microscopic rate constants.

pH Dependence of Amyloid-β Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes.

Central to Alzheimer's disease (AD) is the assembly of the amyloid-beta peptide (Aβ) into fibrils. A reduction in pH accompanying inflammation or subcellular compartments, may accelerate fibril formation as the pH approaches Aβ's isoelectric point (pI). Using global fitting of fibril formation kinetics over a range of pHs, we identify the impact net charge has on individual fibril assembly microscopic rate constants.

Therapeutic potential for amyloid surface inhibitor: only amyloid-β oligomers formed by secondary nucleation disrupt lipid membrane integrity.

Inhibition of amyloid-β peptide (Aβ) aggregation is a promising therapeutic strategy for Alzheimer's disease (AD), as Aβ aggregation is generally believed to trigger AD pathology. Pre-fibril Aβ-oligomers induce membrane disruption and are crucial to neurotoxicity. We have previously designed a short peptide called cyclic helical amyloid surface inhibitor (cHASI) that can selectively bind to the Aβ fibril surface.

Cross-seeding of WT amyloid-β with Arctic but not Italian familial mutants accelerates fibril formation in Alzheimer's disease.

Alzheimer's disease (AD) involves the neurotoxic self-assembly of a 40 and 42 residue peptide, Amyloid-β (Aβ). Inherited early-onset AD can be caused by single point mutations within the Aβ sequence, including Arctic (E22G) and Italian (E22K) familial mutants. These mutations are heterozygous, resulting in an equal proportion of the WT and mutant Aβ isoform expression.

3D-visualization of amyloid-β oligomer interactions with lipid membranes by cryo-electron tomography.

Amyloid-β (Aβ) assemblies have been shown to bind to lipid bilayers. This can disrupt membrane integrity and cause a loss of cellular homeostasis, that triggers a cascade of events leading to Alzheimer's disease. However, molecular mechanisms of Aβ cytotoxicity and how the different assembly forms interact with the membrane remain enigmatic.

Copper Binding to α-Synuclein. Histidine50 Can Form a Ternary Complex with Cu at the N-Terminus but Not a Macrochelate.

α-Synuclein (αSyn) forms amyloid fibrils in the neurons of Parkinson's disease (PD) patients'. Despite a role for Cu in accelerating αSyn fibril formation, coupled with reports of copper dis-homeostasis in PD, there remain controversies surrounding the coordination geometry of Cu with αSyn. Here we compare visible circular dichroism (CD) spectra of Cu loaded on to full-length αSyn together with four peptides that model aspects of Cu binding to the N-terminus and histidine50 of αSyn.

Amyloid-β oligomers have a profound detergent-like effect on lipid membrane bilayers, imaged by atomic force and electron microscopy.

The ability of amyloid-β peptide (Aβ) to disrupt membrane integrity and cellular homeostasis is believed to be central to Alzheimer's disease pathology. Aβ is reported to have various impacts on the lipid bilayer, but a clearer picture of Aβ influence on membranes is required. Here, we use atomic force and transmission electron microscopies to image the impact of different isolated Aβ assembly types on lipid bilayers.

Copper Redox Cycling Inhibits Aβ Fibre Formation and Promotes Fibre Fragmentation, while Generating a Dityrosine Aβ Dimer.

Oxidative stress and the formation of plaques which contain amyloid-β (Aβ) peptides are two key hallmarks of Alzheimer's disease (AD). Dityrosine is found in the plaques of AD patients and Aβ dimers have been linked to neurotoxicity. Here we investigate the formation of Aβ dityrosine dimers promoted by Cu Fenton reactions.

Prion protein stabilizes amyloid-β (Aβ) oligomers and enhances Aβ neurotoxicity in a model of Alzheimer's disease.

The cellular prion protein (PrP) can act as a cell-surface receptor for β-amyloid (Aβ) peptide; however, a role for PrP in the pathogenesis of Alzheimer's disease (AD) is contested. Here, we expressed a range of Aβ isoforms and PrP in the brain. We found that co-expression of Aβ and PrP significantly reduces the lifespan, disrupts circadian rhythms, and increases Aβ deposition in the fly brain.

N-Terminally Truncated Amyloid-β Cofibrillizes with its Full-Length Counterpart: Implications for Alzheimer's Disease.

Amyloid-β peptide (Aβ) isoforms of different lengths and aggregation propensities coexist in vivo. These different isoforms are able to nucleate or frustrate the assembly of each other. N-terminally truncated Aβ and Aβ make up one fifth of plaque load yet nothing is known about their interaction with full-length Aβ .

Ion Channel Formation by Amyloid-β42 Oligomers but Not Amyloid-β40 in Cellular Membranes.

A central hallmark of Alzheimer's disease is the presence of extracellular amyloid plaques chiefly consisting of amyloid-β (Aβ) peptides in the brain interstitium. Aβ largely exists in two isoforms, 40 and 42 amino acids long, but a large body of evidence points to Aβ(1-42) rather than Aβ(1-40) as the cytotoxic form. One proposed mechanism by which Aβ exerts toxicity is the formation of ion channel pores that disrupt intracellular Ca homeostasis.

The Rapid Exchange of Zinc(2+) Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu(2+)/Zn(2+) Mixtures.

The misfolding and self-assembly of amyloid-β (Aβ) into oligomers and fibres is fundamental to Alzheimer's disease pathology. Alzheimer's disease is a multifaceted disease. One factor that is thought to have a significant role in disease aetiology is Zn(2+) homeostasis, which is disrupted in the brains of Alzheimer's disease sufferers and has been shown to modulate Alzheimer's symptoms in animal models.

Methionine oxidation reduces lag-times for amyloid-β(1-40) fiber formation but generates highly fragmented fibers.

Oxidative stress and the formation of amyloid plaques containing amyloid-β (Aβ) peptides are two key hallmarks of Alzheimer's disease. A proportion of methionine (Met) at position 35 within Aβ is oxidized to methionine sulphoxide (Met(OX)) within the Alzheimer's plaques. These oxidative processes may be the key to understanding the early stages of Alzheimer's disease.

Endocytosis of the tachykinin neuropeptide, neurokinin B, in astrocytes and its role in cellular copper uptake.

The tachykinin neuropeptide, neurokinin B (NKB), belongs to a family of peptides having diverse roles in the brain. NKB, along with several other tachykinins, has been identified as a copper-binding peptide, however the physiological relevance of the binding is unclear. Previously, NKB was shown to limit the ability of copper to enter astrocytes and disrupt calcium homeostasis and it was thought that the peptide was sequestering the metal extracellularly.

Truncated Amyloid-β(11-40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly.

Alzheimer disease coincides with the formation of extracellular amyloid plaques composed of the amyloid-β (Aβ) peptide. Aβ is typically 40 residues long (Aβ(1-40)) but can have variable C and N termini. Naturally occurring N-terminally truncated Aβ(11-40/42) is found in the cerebrospinal fluid and has a similar abundance to Aβ(1-42), constituting one-fifth of the plaque load.

A Comparison of Three Fluorophores for the Detection of Amyloid Fibers and Prefibrillar Oligomeric Assemblies. ThT (Thioflavin T); ANS (1-Anilinonaphthalene-8-sulfonic Acid); and bisANS (4,4'-Dianilino-1,1'-binaphthyl-5,5'-disulfonic Acid).

Amyloid fiber formation is a key event in many misfolding disorders. The ability to monitor the kinetics of fiber formation and other prefibrillar assemblies is therefore crucial for understanding these diseases. Here we compare three fluorescent probes for their ability to monitor fiber formation, ANS (1-anilinonaphthalene-8-sulfonic acid) and bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid) along with the more widely used thioflavin T (ThT).

Cu²⁺ accentuates distinct misfolding of Aβ₁₋₄₀ and Aβ₁₋₄₂ peptides, and potentiates membrane disruption.

Central to Alzheimer's disease is the misfolding of amyloid-beta (Aβ) peptide, which generates an assorted population of amorphous aggregates, oligomers and fibres. Metal ion homoeostasis is disrupted in the brains of sufferers of Alzheimer's disease and causes heightened Alzheimer's disease phenotype in animal models. In the present study, we demonstrate that substochiometric Cu²⁺ affects the misfolding pathway of Aβ₁₋₄₀, and the more toxic Aβ₁₋₄₂, in markedly different ways.

Bioactivity and structural properties of chimeric analogs of the starfish SALMFamide neuropeptides S1 and S2.

The starfish SALMFamide neuropeptides S1 (GFNSALMFamide) and S2 (SGPYSFNSGLTFamide) are the prototypical members of a family of neuropeptides that act as muscle relaxants in echinoderms. Comparison of the bioactivity of S1 and S2 as muscle relaxants has revealed that S2 is ten times more potent than S1. Here we investigated a structural basis for this difference in potency by comparing the bioactivity and solution conformations (using NMR and CD spectroscopy) of S1 and S2 with three chimeric analogs of these peptides.

Developing predictive rules for coordination geometry from visible circular dichroism of copper(II) and nickel(II) ions in histidine and amide main-chain complexes.

Circular dichroism (CD) spectroscopy in the visible region (vis-CD) is a powerful technique to study metal-protein interactions. It can resolve individual d-d electronic transitions as separate bands and is particularly sensitive to the chiral environment of the transition metals. Modern quantum chemical methods enable CD spectra calculations from which, along with direct comparison with the experimental CD data, the conformations and the stereochemistry of the metal-protein complexes can be assigned.