51 research outputs found
Mixed Ligand Cu<sup>2+</sup> Complexes of a Model Therapeutic with Alzheimer’s Amyloid‑β Peptide and Monoamine Neurotransmitters
8-Hydroxyquinolines
(8HQ) have found widespread application in chemistry and biology due
to their ability to complex a range of transition metal ions. The
family of 2-substituted 8HQs has been proposed for use in the treatment
of Alzheimer’s disease (AD). Most notably, the therapeutic
PBT2 (Prana Biotechnology Ltd.) has been shown to act as an efficient
metal chaperone, disaggregate metal-enriched amyloid plaques comprised
of the Aβ peptide, inhibit Cu/Aβ redox chemistry, and
reverse the AD phenotype in transgenic animal models. Yet surprisingly
little is known about the molecular interactions at play. In this
study, we show that the homologous ligand 2-[(dimethylamino)methyl]-8-hydroxyquinoline
(HL) forms a CuL complex with a conditional (apparent) dissociation
constant of 0.33 nM at pH 6.9 and is capable of forming ternary Cu<sup>2+</sup> complexes with neurotransmitters including histamine (HA),
glutamic acid (Glu), and glycine (Gly), with glutathione disulfide
(GSSG), and with histidine (His) side chains of proteins and peptides
including the Aβ peptide. Our findings suggest a molecular basis
for the strong metal chaperone activity of PBT2, its ability to attenuate
Cu<sup>2+</sup>/Aβ interactions, and its potential to promote
neuroprotective and neuroregenerative effects
Comparison between the multiple-atlas and ten single-atlas approaches subject by subject (left: error ratio; right: correlation).
<p>The red line corresponds to the proposed multiple-atlas approach, while the rest ten lines correspond to the ten single-atlas approaches in comparison, respectively. To improve clarity, the subjects' IDs are sorted according to the increase of error ratios and correlation, respectively.</p
Comparison of the multiple-atlas and ten single-atlas approaches over AAL ROIs within PiB- group (left: error ratio; right: correlation).
<p>The red line corresponds to the proposed multiple-atlas approach, while the rest ten lines correspond to the ten single-atlas approaches in comparison, respectively. To improve clarity, not all ROI names are shown in the graph.</p
Comparison of Z-score Estimation between the PET-only and the MRI-dependent Methods (averaging over 123 subjects that are not in the atlas set).
<p>Comparison of Z-score Estimation between the PET-only and the MRI-dependent Methods (averaging over 123 subjects that are not in the atlas set).</p
Vertex-based mean estimation errors (ratio) in each AAL ROI.
<p>The errors are visualized on an inflated template brain surface for both PiB+ and PiB- groups. There are higher estimation error ratios for PiB- group than for PiB+ group, due to the minimal amount of retention and the reduced dynamic range of PiB- group. The mean absolute estimation error (vertex-based) is 0.19±0.03 for PiB- group and 0.23±0.04 for PiB+ group as reported in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084777#pone-0084777-t003" target="_blank">Table 3</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084777#pone-0084777-t004" target="_blank">Table 4</a>.</p
Comparison between MRI-dependent and PET-only methods for PiB- group (averaging over 123 subjects that are not included in the atlas set).
<p>Comparison between MRI-dependent and PET-only methods for PiB- group (averaging over 123 subjects that are not included in the atlas set).</p
Illustration of the MRI-dependent method.
<p>The PiB retention is measured in the PET image within its grey matter mask obtained from MRI tissue segmentation, and averaged along the normal direction of the GM-WM interface (overlaid on the PET image) extracted from the subject's MRI. The mean PiB value for each surface vertex is mapped onto the surface for visualization.</p
Visual Inspection for PiB measurements.
<p>Surface-based PiB measurements from the MRI-dependent method (the top row) and the proposed method (the bottom row) for four examples: (a) AD, (b) PiB+ NC, (c) PiB+ NC, and (d) PiB- NC.</p
Comparison of the multiple-atlas and ten single-atlas approaches over AAL ROIs within PiB+ group (left: error ratio; right: correlation).
<p>The red line corresponds to the proposed multiple-atlas approach, while the rest ten lines correspond to the ten single-atlas approaches in comparison, respectively. To improve clarity, not all ROI names are shown in the graph.</p
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