P2‐001: High‐resolution magnetic resonance imaging to quantify relaxation parameters in Alzheimer's brain tissue

Collingwood, Joanna F.; Chandra, Saurav; Davidson, Mark R.; Mikhaylova, Albina; Eskin, Thomas A.; Dobson, Jon; Forder, John R.; Batich, Christopher D.

doi:10.1016/j.jalz.2008.05.1081

Cited by 2 publications

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“…Inhibition of polymorphic Aβ aggregation is a promising approach to developing effective therapeutic agents for AD. ,− In this context, we studied the effect of our compounds 1 – 4 on metal-independent and -dependent Aβ42 aggregation, and compounds 1 – 4 showed minimal ThT fluorescence (24%, 17%, 26% and 18%, respectively) in comparison to that of Aβ42 alone, which is considered as 100%; GHK exhibited 78% ThT fluorescence (Figure S15). The data also revealed that the most promising antioxidant 4 inhibited Aβ42 aggregation by >80% compared to ∼20% by GHK.…”

Section: Results and Discussionmentioning

confidence: 99%

Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer’s Disease

Samanta

Rajasekhar

Babagond

et al. 2019

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is one of the most devastating forms of dementia, without reliable treatments to cure, delay the onset, or prevent the disease progression. The proposed toxic mechanisms of AD include amyloidogenesis of amyloid β (Aβ), metal ion dyshomeostasis, redox active metal−Aβ inclusion complex formation, and generation of excessive reactive oxygen and nitrogen species (ROS and RNS). The imbalance in redox homeostasis causes oxidative stress, DNA damage, mitochondrial dysfunction, and inflammation, which collectively become a major hurdle in the development of effective therapeutic agents for multifactorial AD. This necessitates a multifunctional strategy to develop effective therapeutic agents to inhibit multifaceted toxicity. In this context, we report a rational design, synthesis, and detailed study to identify a small molecule multifunctional modulator (MFM) inspired by the human origin tripeptide. The lead, MFM 4, chelates and sequesters metal ions, disrupts their redox cycles, prevents excessive ROS production and oxidative stress, ameliorates oxidative DNA damage and mitochondrial dysfunction, and modulates Nrf2 protein signaling under oxidative stress conditions by eliminating the toxic stress elements. The MFM 4 was found to inhibit metal-dependent and -independent Aβ aggregation and qualified as a suitable candidate to inhibit Aβ-induced neuronal toxicity. The NMR spectroscopy study revealed molecular-level interactions of 4 with Aβ42, which explain the mechanism of aggregation inhibition. Furthermore, 4 effectively inhibited inflammation as revealed by reduction in nitric oxide (NO) production in LPS-activated glial cells. These key features make 4 a potential MFM platform to develop therapeutic agents for metal (Cu, Zn and Fe)-dependent and -independent multifaceted Aβ toxicity of AD.

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Section: Results and Discussionmentioning

confidence: 99%

Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer’s Disease

Samanta

Rajasekhar

Babagond

et al. 2019

ACS Chem. Neurosci.

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“…As there is significant heterogeneity in the microstructural distribution and bound states of iron [as observed in hippocampus ( Antharam et al, 2012 ) and SN ( Blazejewska et al, 2013 )], there is value in being able to directly describe the spatial relationship between iron and MRI. Given the limited sensitivity of routine iron histochemistry for this purpose [recently noted in postmortem analysis of iron and MRI in the SN ( Blazejewska et al, 2013 )], there have been growing efforts to correlate SXRF microscopy maps with the corresponding MRI data from post-mortem human tissue ( Collingwood et al, 2008a ; Hopp et al, 2010 ; Antharam et al, 2012 ). This has included studies in formalin-fixed tissue to achieve approximate correlations between susceptibility-weighted imaging (SWI) and iron maps for multiple anatomical regions in each case via the rapid SXRF approach ( Hopp et al, 2010 ), and for the first time in unfixed tissues, working at high spatial resolution in thin sections to match SXRF iron maps with R 2 and R 2 * maps, permitting detailed analysis of the hippocampus in AD cases and age-matched controls and demonstration of a positive correlation between iron and R 2 , R 2 * ( Antharam et al, 2012 ).…”

Section: X-ray Fluorescence Analysis Of Iron In Neurodegenerative Dismentioning

confidence: 99%

The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light

Collingwood¹,

Davidson²

2014

Front. Pharmacol.

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There is evidence for iron dysregulation in many forms of disease, including a broad spectrum of neurodegenerative disorders. In order to advance our understanding of the pathophysiological role of iron, it is helpful to be able to determine in detail the distribution of iron as it relates to metabolites, proteins, cells, and tissues, the chemical state and local environment of iron, and its relationship with other metal elements. Synchrotron light sources, providing primarily X-ray beams accompanied by access to longer wavelengths such as infra-red, are an outstanding tool for multi-modal non-destructive analysis of iron in these systems. The micro- and nano-focused X-ray beams that are generated at synchrotron facilities enable measurement of iron and other transition metal elements to be performed with outstanding analytic sensitivity and specificity. Recent developments have increased the scope for methods such as X-ray fluorescence mapping to be used quantitatively rather than semi-quantitatively. Burgeoning interest, coupled with technical advances and beamline development at synchrotron facilities, has led to substantial improvements in resources and methodologies in the field over the past decade. In this paper we will consider how the field has evolved with regard to the study of iron in proteins, cells, and brain tissue, and identify challenges in sample preparation and analysis. Selected examples will be used to illustrate the contribution, and future potential, of synchrotron X-ray analysis for the characterization of iron in model systems exhibiting iron dysregulation, and for human cases of neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis.

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P2‐001: High‐resolution magnetic resonance imaging to quantify relaxation parameters in Alzheimer's brain tissue

Abstract: 2016-12-24T18:07:49

Cited by 2 publications

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Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer’s Disease

Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer’s Disease

The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light

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