Simon C. Drew

Bio: Simon C. Drew is an academic researcher from University of Melbourne. The author has contributed to research in topics: Electron paramagnetic resonance & Amyloid beta. The author has an hindex of 23, co-authored 74 publications receiving 2105 citations. Previous affiliations of Simon C. Drew include Polish Academy of Sciences & Monash University.

Pleomorphic copper coordination by Alzheimer's disease amyloid-beta peptide.

Abstract: Numerous conflicting models have been proposed regarding the nature of the Cu2+ coordination environment of the amyloid β (Aβ) peptide, the causative agent of Alzheimer’s disease This study used multifrequency CW-EPR spectroscopy to directly resolve the superhyperfine interactions between Cu2+ and the ligand nuclei of Aβ, thereby avoiding ambiguities associated with introducing point mutations Using a library of Aβ16 analogues with site-specific 15N-labeling at Asp1, His6, His13, and His14, numerical simulations of the superhyperfine resonances delineated two independent 3N1O Cu2+ coordination modes, {NaD1, O, NeH6, NeH13} (component Ia) and {NaD1, O, NeH6, NeH14} (component Ib), between pH 6−7 A third coordination mode (component II) was identified at pH 80, and simulation of the superhyperfine resonances indicated a 3N1O coordination sphere involving nitrogen ligation by His6, His13, and His14 No differences were observed upon 17O-labeling of the phenolic oxygen of Tyr10, confirming it is not a key

Alanine-2 carbonyl is an oxygen ligand in Cu2+ coordination of Alzheimer's disease amyloid-beta peptide--relevance to N-terminally truncated forms.

Abstract: Copper interactions with the beta-amyloid peptide (Abeta) are believed to play a role in Alzheimer's disease (AD), in particular due to production of reactive oxygen species and Cu(2+)-mediated oligomerization. To understand the role that copper might play in these processes, a detailed knowledge of the fundamental Cu(2+)/Abeta interactions is essential. To date, the identity of the oxygen ligand(s) involved in Cu(2+) coordination by Abeta has remained unclear. Here, we have used site-specific (13)C and (15)N labeling in conjunction with hyperfine sublevel correlation (HYSCORE) spectroscopy to unambiguously identify the carbonyl of Alanine-2 as an oxygen ligand in one of the pH-dependent Cu(2+) coordination modes of Abeta. Polarization of the carbonyl moiety by Cu(2+) could promote amide hydrolysis and cleavage of the peptide bond between Ala2 and Glu3, providing a chemical mechanism for the generation of truncated Abeta 3-40/42 species found in AD plaques.

The heterogeneous nature of Cu2+ interactions with Alzheimer's amyloid-β peptide.

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive and memory impairment. Within the brain, senile plaques, which comprise extracellular deposits of the amyloid-β peptide (Aβ), are the most common pathological feature of AD. A high concentration of Cu2+ is found within these plaques, which are also areas under oxidative stress. Laboratory work has shown that in vitro Aβ will react with Cu2+ to induce peptide aggregation and the production of reactive oxygen species. As such, this interaction offers a possible explanation for two of the defining pathological features observed in the AD brain: the presence of amyloid plaques, which consist largely of insoluble Aβ aggregates, and the abundant oxidative stress therein. Researchers have accordingly put forth the “metals hypothesis” of AD, which postulates that compounds designed to inhibit Cu2+/Aβ interactions and redistribute Cu2+ may offer therapeutic potential for treating AD.Characterization of the pH-dependent ...

Cu2+ binding modes of recombinant alpha-synuclein--insights from EPR spectroscopy.

Abstract: The interaction of the small (140 amino acid) protein, alpha-synuclein (alphaS), with Cu(2+) has been proposed to play a role in Parkinson's disease (PD). While some insight from truncated model complexes has been gained, the nature of the corresponding Cu(2+) binding modes in the full length protein remains comparatively less well characterized. This work examined the Cu(2+) binding of recombinant human alphaS using Electron Paramagnetic Resonance (EPR) spectroscopy. Wild type (wt) alphaS was shown to bind stoichiometric Cu(2+) via two N-terminal binding modes at physiological pH. An H50N mutation isolated one binding mode, whose g parallel, A parallel, and metal-ligand hyperfine parameters correlated well with a {NH2, N(-), beta-COO(-), H2O} mode previously identified in truncated model fragments. Electron spin-echo envelope modulation (ESEEM) studies of wt alphaS confirmed the second binding mode at pH 7.4 involved coordination of His50 and its g parallel and A parallel parameters correlated with either {NH2, N(-), beta-COO(-), N(Im)} or {N(Im), 2 N(-)} coordination observed in alphaS fragments. At pH 5.0, His50-anchored Cu(2+) binding was greatly diminished, while {NH2, N(-), beta-COO(-), H2O} binding persisted in conjunction with another two binding modes. Metal-ligand hyperfine interactions from one of these indicated a 1N3O coordination sphere, which was ascribed to a {NH2, CO} binding mode. The other was characterized by a spectrum similar to that previously observed for diethylpyrocarbonate-treated alphaS and was attributed to C-terminal binding centered on Asp121. In total, four Cu(2+) binding modes were identified within pH 5.0-7.4, providing a more comprehensive picture of the Cu(2+) binding properties of recombinant alphaS.

Proceedings of the National Academy of Sciences

Abstract: where A represents the magnetic vector potential, is an integral of the hydromagnetic equations. This -integral made it possible to formulate a variational principle for the force-free magnetic fields. The integral expresses the fact that motions cannot transform a given field in an entirely arbitrary different field, if the conductivity of the medium isconsidered infinite. In this paper we shall show that the full set of hydromagnetic equations admit five more integrals, besides the energy integral, if dissipative processes are absent. These integrals, as we shall presently verify, are I2 =fbHvdV, (2)

The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes

Abstract: The 'toxic Aβ oligomer' hypothesis has attracted considerable attention among Alzheimer's disease researchers as a way of resolving the lack of correlation between deposited amyloid-β (Aβ) in amyloid plaques-in terms of both amount and location-and cognitive impairment or neurodegeneration. However, the lack of a common, agreed-upon experimental description of the toxic Aβ oligomer makes interpretation and direct comparison of data between different research groups impossible. Here we critically review the evidence supporting toxic Aβ oligomers as drivers of neurodegeneration and make some suggestions that might facilitate progress in this complex field.

Oxidative stress and the amyloid beta peptide in Alzheimer's disease.

Abstract: Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

Abstract: Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.