Copper Homeostasis and Neurodegenerative Disorders (Alzheimer's, Prion, and Parkinson's Diseases and Amyotrophic Lateral Sclerosis)

Alzheimer’s amyloid fibrils: structure and assembly

IW Hamley Chemical reviews, 2012 ACS Publications ... the γ-secretase complex and its cell surface localization, in the absence of an effect on Notch ... in the development of effective γ-secretase inhibitors is to avoid side-effects caused by ... EP2 receptor.(79) Prostaglandin E 2 is produced during inflammation due to activity by cytosolic ... Cited by 143 Related articles All 4 versions Cite Save

/pdf/the-amyloid-beta-peptide-a-chemist-s-perspective-role-in-45cfs3lkvz.pdf

The amyloid beta peptide: a chemist's perspective. Role in Alzheimer's and fibrillization.

Oxidative stress, manifested by protein oxidation, lipid peroxidation, DNA oxidation and 3-nitrotyrosine formation, among other indices, is observed in Alzheimer's disease (AD) brain. Amyloid beta-peptide (1-42) [Abeta(1-42)] may be central to the pathogenesis of AD. Our laboratory and others have implicated Abeta(1-42)-induced free radical oxidative stress in the neurodegeneration observed in AD brain. This paper reviews some of these studies from our laboratory. Recently, we showed both in-vitro and in-vivo that methionine residue 35 (Met-35) of Abeta(1-42) was critical to its oxidative stress and neurotoxic properties. Because the C-terminal region of Abeta(1-42) is helical, and invoking the i + 4 rule of helices, we hypothesized that the carboxyl oxygen of lle-31, known to be within a van der Waals distance of the S atom of Met-35, would interact with the latter. This interaction could alter the susceptibility for oxidation of Met-35, i.e. free radical formation. Consistent with this hypothesis, substitution of lle-31 by the helix-breaking amino acid, proline, completely abrogated the oxidative stress and neurotoxic properties of Abeta(1-42). Removal of the Met-35 residue from the lipid bilayer by substitution of the negatively charged Asp for Gly-37 abrogated oxidative stress and neurotoxic properties of Abeta(1-42). The free radical scavenger vitamin E prevented A(beta (1-42)-induced ROS formation, protein oxidation, lipid peroxidation, and neurotoxicity in hippocampal neurons, consistent with our model for Abeta-associated free radical oxidative stress induced neurodegeneration in AD. ApoE, allele 4, is a risk factor for AD. Synaptosomes from apoE knock-out mice are more vulnerable to Abeta-induced oxidative stress (protein oxidation, lipid peroxidation, and ROS generation) than are those from wild-type mice. We also studied synaptosomes from allele-specific human apoE knock-in mice. Brain membranes from human apoE4 mice have greater vulnerability to Abeta(1-42)-induced oxidative stress than brain membranes from apoE2 or E3, assessed by the same indices, consistent with the notion of a coupling of the oxidative environment in AD brain and increased risk of developing this disorder. Using immunoprecipitation of proteins from AD and control brain obtained no longer than 4h PMI, selective oxidized proteins were identified in the AD brain. Creatine kinase (CK) and beta-actin have increased carbonyl groups, an index of protein oxidation, and Glt-1, the principal glutamate transporter, has increased binding of the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE). Abeta inhibits CK and causes lipid peroxidation, leading to HNE formation. Implications of these findings relate to decreased energy utilization, altered assembly of cytoskeletal proteins, and increased excitotoxicity to neurons by glutamate, all reported for AD. Other oxidatively modified proteins have been identified in AD brain by proteomics analysis, and these oxidatively-modified proteins may be related to increased excitotoxicity (glutamine synthetase), aberrant proteasomal degradation of damaged or aggregated proteins (ubiquitin C-terminal hydrolase L-1), altered energy production (alpha-enolase), and diminished growth cone elongation and directionality (dihydropyrimindase-related protein 2). Taken together, these studies outlined above suggest that Met-35 is key to the oxidative stress and neurotoxic properties of Abeta(1-42) and may help explain the apoE allele dependence on risk for AD, some of the functional and structural alterations in AD brain, and strongly support a causative role of Abeta(1-42)-induced oxidative stress and neurodegeneration in AD.

Amyloid β-peptide (1-42)-induced Oxidative Stress and Neurotoxicity: Implications for Neurodegeneration in Alzheimer's Disease Brain. A Review

Filamentous inclusions made of alpha-synuclein constitute the defining neuropathological characteristic of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Rare familial cases of Parkinson's disease are associated with mutations A53T and A30P in alpha-synuclein. We report here the assembly properties and secondary structure characteristics of recombinant alpha-synuclein. Carboxy-terminally truncated human alpha-synuclein (1-87) and (1-120) showed the fastest rates of assembly, followed by human A53T alpha-synuclein, and rat and zebra finch alpha-synuclein. Wild-type human alpha-synuclein and the A30P mutant showed slower rates of assembly. Upon shaking, filaments formed within 48 h at 37 degrees C. The related proteins beta- and gamma-synuclein only assembled after several weeks of incubation. Synthetic human alpha-synuclein filaments were decorated by an antibody directed against the carboxy-terminal 10 amino acids of alpha-synuclein, as were filaments extracted from dementia with Lewy bodies and multiple system atrophy brains. Circular dichroism spectroscopy indicated that alpha-synuclein undergoes a conformational change from random coil to beta-sheet structure during assembly. X-ray diffraction and electron diffraction of the alpha-synuclein assemblies showed a cross-beta conformation characteristic of amyloid.

https://www.pnas.org/content/pnas/97/9/4897.full.pdf

Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation.

Publisher Summary The immense difficulties and unexpected questions presented by hundreds of amyloid toxicity studies beg for a careful study of A β assembly processes, evaluating the kinetics and structures of different aggregation pathways that convert the soluble monomer into the higher order A β assemblies that harbor neurotoxic properties. A large array of sophisticated instrumental techniques, including analytical ultracentrifugation, atomic force microscopy, solid-state and solution NMR, and fluorescence tracer techniques, will help elucidate the bioactive A β structure(s), whereas specific cellular and biochemical techniques will elucidate the specific steps involved in the aftermath of A β cellular interactions. Nonetheless, all these potentially useful high technology methods are ineffective unless proper care regarding A β sample preparation is taken into account. This chapter briefly summarizes potential problems involved with A β sample preparation and has also described methods to deal with these issues. The most critical complications are related to the starting structures and aggregation states of the A β .

Methodological and chemical factors affecting amyloid beta peptide amyloidogenicity.

Major problems exist with pharmacological and biophysical studies of the synthetic β(1-42) peptide, in that the results often lack reproducibility. The starting aggregation states and structures of the various synthetic commercial lots appear to vary, resulting in signijicant lot-to-lot variability. We describe here an easy, efficient trifluoroacetic acid (TFA) pretreatment method that renders the Aβ easily soluble both in aqueous, buffered solutions and in organic solvents such as hexafluoroisopropanol (HFIP) or dimethylsulfoxide (DMSO). The TFA treated Aβ exhibits the properties of monomeric, random coil structures and lacks pre-aggregated material that can act as seeds in fibrilization assays, thus reducing the batch to batch variation. In addition, nuclear magnetic resonance (NMR) spectra recorded in deuterated TFA allow measurement of the peptide purity that is not obtainable with other analytical methods.

Trifluoroacetic acid pretreatment reproducibly disaggregates the amyloid β-peptide

Amyloid AB (1–40) and AB(1–42) adopt remarkably stable, monomeric, and extended structures in water solution at neutral pH

743 The solution structure of the amyloid β-(1–42) peptide provides a molecular approach for the treatment of Alzheimer's Disease

The aggregation of the β-peptide into amyloid is a key pathological event in Alzheimer's disease. This process (β-amyloidosis) involves the conversion of soluble random coil, α-helical or β-sheet conformations into insoluble, aggregated β-pleated sheet structures. The pH is a significant extrinsic factor that influences β-amyloidosis, which must be related to the presence of ionizable groups in the β-peptide. To further evaluate this effect, we determined the dissociation constants (pKa) of the side chains for the aspartic acid (Asp), glutamic acid (Glu), histidine (His), and tyrosine (Tyr) amino acid residues using NMR spectroscopy. The measurements were performed under different solution conditions, where the predominant conformation is either random coil or α-helix. We have used a peptide fragment that comprises residues 1−28 [β-(1−28)] of the natural β-(1−40) or β-(1−42) peptides, which is an appropriate model since the remaining 29−40 or 29−42 regions are devoid of polar and charged amino acid residu...

/pdf/residue-specific-pka-measurements-of-the-b-peptide-and-129w85tnej.pdf

Residue-Specific pKa Measurements of the β-Peptide and Mechanism of pH-Induced Amyloid Formation

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