Role of Metals in Alzheimer Disease

Roberts, Blaine R.; Bush, Ashley I.

doi:10.1002/9780470572702.ch24

Cited by 2 publications

(2 citation statements)

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“…Amyloid toxicity is a known pathway of cell death postulated to play a role in the development of Alzheimer’s disease . The toxicity of amyloid is known to be amplified due to the interaction of metal ions with the peptide, which induces the productions of ROS and amyloid aggregation. − The effect of molecule 1 on the interaction of copper(II) with Aβ proteins was measured using the intrinsic fluorescent signal of the Tyr-10 residue of the Aβ 1–40 protein. − The Tyr-10 signal has been shown to be decreased by the addition of copper(II) and other transition-metal ions. ,− Under the conditions used in this study, the addition of copper(II) to Aβ 1–40 results in a 56% decrease of the Tyr-10 fluorescence (Figure ). However, a 13% increase in the fluorescent signal is obtained by the addition of molecule 1 to the solution of Aβ 1–40 + copper(II).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule

González

Pota

Turan

et al. 2017

ACS Chem. Neurosci.

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Metal-ion misregulation and oxidative stress continue to be components of the continually evolving hypothesis describing the molecular origins of Alzheimer's disease. Therefore, these features are viable targets for synthetic chemists to explore through hybridizations of metal-binding ligands and antioxidant units. To date, the metal-binding unit in potential therapeutic small molecules has largely been inspired by clioquinol with the exception of a handful of heterocyclic small molecules and open-chain systems. Heterocyclic small molecules such as cyclen (1,4,7,10-tetraazacyclododecane) have the advantage of straightforward N-based modifications, allowing the addition of functional groups. In this work, we report the synthesis of a triazine bridged system containing two cyclen metal-binding units and an antioxidant coumarin appendage inspired by nature. This new potential therapeutic molecule shows the ability to bind copper in a unique manner compared to other chelates proposed to treat Alzheimer's disease. DPPH and TEAC assays exploring the activity of N-(2-((4,6-di(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)amino)ethyl)-2-oxo-2H-chromene-3-carboxamide (molecule 1) show that the molecule is antioxidant. Cellular studies of molecule 1 indicate a low toxicity (EC = 80 μM) and the ability to protect HT-22 neuronal cells from cell death induced by Aβ + copper(II), thus demonstrating the potential for molecule 1 to serve as a multimodal therapeutic for Alzheimer's disease.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule

González

Pota

Turan

et al. 2017

ACS Chem. Neurosci.

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“…metal-mediated oxidative damage) must be the cause of Ab aggregation that leads to the development of AD. The ''metal hypothesis of AD'' has been consequently proposed, 7,[16][17][18][19] according to which the abnormal interaction between Ab and metal ions has to be considered as one of the major culprits for the development of AD. Therefore, many new molecules targeting Ab-metal interactions have been proposed as possible drugs for treatment of the disease, many of which have been also advanced through clinical trials.…”

Section: Metallomicsmentioning

confidence: 99%

Metallostasis and amyloid β-degrading enzymes

2012

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Amyloid-Beta (Aβ) is a major constituent of senile plaques and one of the principle hallmarks of Alzheimer's disease (AD). The peptide is produced by proteolytic cleavage of the larger amyloid precursor protein (APP). Increased production and aggregation of the peptide are associated with pathology. Emerging evidence suggests that the steady-state levels of Aβ are determined by the balance between its production and degradation. For this reason, the tuning of the activity of enzymes that degrade Aβ may be a promising approach in the development of novel therapeutics aimed at reducing Aβ concentration by enhancing its removal. A great part of Aβ degrading enzymes are known to be metalloproteases. In the last decade increasing evidence supported the idea that metal ion homeostasis is affected in several regions of AD brain and metals play an important role in tuning enzyme activity. There are three main different pathways by which metal ions can affect the proteolytic enzymes responsible for Aβ peptides degradation, as metal ions can: (i) form complexes with Aβ peptides that are not easily degraded; (ii) directly bind to degradative enzymes; (iii) produce signalling cascades that alter enzymes activity involved in Aβ catabolism. In the current literature the three points mentioned above are very often puzzled, resulting in a quite fragmentary scenario. The aim of this work is to find a link between metal ion homeostasis and Aβ degradation by separating and analysing the three different pathways proposed.

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Role of Metals in Alzheimer Disease

Cited by 2 publications

References 84 publications

Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule

Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule

Metallostasis and amyloid β-degrading enzymes

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