The Role of Metals in &amp;#946; -Amyloid Peptide Aggregation: X-Ray Spectroscopy and Numerical Simulations

Morante, Silvia

doi:10.2174/156720508786898505

Cited by 30 publications

(33 citation statements)

References 65 publications

(122 reference statements)

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“…[74], an interesting pattern of strong similarities and differences emerge that are summarized below where the equality sign means identity (within errors) of spectral features (see Figs. (2) and (3) in [40]). On the basis of the previous comparison, discussion and fitting of the data have been limited to the following samples …”

Section: Discussionmentioning

confidence: 96%

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Metals in Alzheimer’s Disease: A Combined Experimental and Numerical Approach

Rossi

2014

Advances in Alzheimer's Research

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Abstract:Alzheimer disease is a pathology causing severe problems with memory, thinking and behavior. It accounts for the majority of dementia cases and is the sixth leading cause of death in developed countries. Unfortunately a real cure is still missing and the drug treatments today available can only reduce symptoms. It belongs to a large class of diseases, called amyloidosis, in which endogenous proteins or peptides undergo a misfolding process switching from the physiological soluble configuration to a pathological fibrillar insoluble state. An important, but not yet fully elucidated, rôle appears to be played in these processes by transition metals (mainly copper and zinc) that have been observed to be present in fairly large amounts in patient's neurological plaques. In this review we will show that the challenging problem of understanding the physico-chemical basis of protein misfolding and aggregation can be successfully investigated with a combination of modern spectroscopic techniques and advanced first principle numerical simulations. In particular, it will be shown that different metals can rival in peptide binding thus adding support to the hypothesis that metal dyshomeostasis may be relevant in the Alzheimer disease development.

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Section: Discussionmentioning

confidence: 96%

“…For a pictorial description of the behaviour of the electron wave function and the corresponding measured XAS signal see Fig. 1 in [40] in the case of an isolated atomic absorber (left panel), and in the case of an absorber surrounded by other atoms acting as scattering centers (right panel).…”

Section: X-ray Absorption Spectroscopymentioning

confidence: 99%

Metals in Alzheimer’s Disease: A Combined Experimental and Numerical Approach

Rossi

2014

Advances in Alzheimer's Research

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“…[17][18][19][20][21][22][23][24][25][26][27][28] Metal ions are involved in the aggregation of ABri and ADan peptides as well. 20 On the other hand nothing is known about the metal binding abilities of Bri2-23 and more importantly whether metal ions affect its structure and aggregation ability.…”

Section: Introductionmentioning

confidence: 99%

Metal ion mediated transition from random coil to β-sheet and aggregation of Bri2-23, a natural inhibitor of Aβ aggregation

et al. 2015

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Furin-dependent maturation of the BRI2 protein generates the Bri2-23 fragment that is able to arrest the aggregation of amyloidβ, the peptide implicated in Alzheimer's disease (AD). Bri2-23 contains cysteines at positions 5 and 22, which are likely to bind to metal ions such as Cu(i). Metal ions may play a role in the etiology of neurodegenerative disorders such as AD, and in this work we explore the metal ion induced folding and aggregation of Bri2-23 using Hg(ii) and Ag(i) as spectroscopic probes with structural and ligand preferences similar to those of Cu(i), while not displaying redox activity under the experimental conditions. In general, interaction of Bri2-23 with soft metal ions changes the structural properties and solution behavior of the peptide that tune to increasing metal to peptide stoichiometry. Potentiometric, (199m)Hg PAC and ESI-MS data indicate that addition of up to 0.5 equivalents of Hg(ii) to Bri2-23 yields a two-coordinated HgS2 structure at the metal site. While the free peptide is inherently unstructured, the presence of Ag(i) and Hg(ii) gives rise to β-sheet formation. NMR spectroscopy supports the formation of β-sheet structure in the presence of 0.5 equivalents of Hg(ii), and displays an interesting and marked change in the TOCSY spectra when increasing the Hg(ii) to peptide stoichiometry from 0.5 to 0.7 equivalents, indicating the equilibrium between two structural analogues of the complex. Addition of more than 0.7 equivalents of Hg(ii) gives rise to line broadening, presumably reflecting aggregation. This is further supported by ThT fluorescence studies showing that the Bri2-23 peptide does not aggregate over 24 hours, while addition of over 0.7 equivalents of Ag(i) or Hg(ii) leads to increase of fluorescence, indicating that these metal ions induce aggregation. Thus, a model integrating all data into a coherent picture is that the metal ion binding to the two thiolates gives rise to folding of the peptide into a structure that is prone to aggregation, forming aggregates with a considerable amount of β-sheets. Molecular dynamics simulations initiated with structures that agree with NMR data additionally support this model.

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“…[11][12][13][14][15] The interaction of redox active metal ions (i.e., Fe 3+ and Cu 2+ ) with Aβ might also lead to the formation of reactive oxygen species, which typifies AD neuropathology and precedes Aβ deposition in AD. 8,[16][17][18] In particular, the roles of zinc and copper in AD have been investigated in great detail by nuclear magnetic resonance (NMR), [19][20][21][22][23] electron paramagnetic resonance (EPR), 19, 24 X-ray absorption spectroscopy, [25][26] Fourier transform infrared spectroscopy, 7,27 theoretical modeling, 9,[28][29][30][31] and so on.…”

Section: Introductionmentioning

confidence: 99%

Interaction of Metal Ions with the His13-His14 Sequence Relevant to Alzheimer’s Disease

et al. 2015

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The interaction of a series of metal ions (i.e., groups 1 and 2, first-row transition metals, and groups 11-14) with the His13-His14 sequence relevant to Alzheimer's disease has been studied using quantum chemical calculations. Metal ions prefer to occupy three coordination sites at two Nδ of the imidazole rings and one carbonyl oxygen. Simulated IR spectra reveal that vibrational frequency of C-O stretch affords a sensitive probe for understanding the interaction of His13-His14 with metal ions. The relative strength of the interaction of His13-His14 with the representative metal ions follows the order of K(+) < Ca(2+) < Zn(2+) < Cu(2+) < Fe(3+) < Al(3+), which is closely correlated with the available experimental results, providing a vivid physical picture about how metal ions bind to amyloid β-peptide. IR spectra of the [M·(His13-His14)](n+) complexes could be measured by infrared photodissociation spectroscopic technique and thus afford useful information for the understanding of structure-function relationship and the design of suitable drugs.

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The Role of Metals in β -Amyloid Peptide Aggregation: X-Ray Spectroscopy and Numerical Simulations

Cited by 30 publications

References 65 publications

Metals in Alzheimer’s Disease: A Combined Experimental and Numerical Approach

Metals in Alzheimer’s Disease: A Combined Experimental and Numerical Approach

Metal ion mediated transition from random coil to β-sheet and aggregation of Bri2-23, a natural inhibitor of Aβ aggregation

Interaction of Metal Ions with the His13-His14 Sequence Relevant to Alzheimer’s Disease

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