The chemistry of Alzheimer’s disease

Rauk, Arvi

doi:10.1039/b807980n

Cited by 393 publications

(528 citation statements)

References 242 publications

(316 reference statements)

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“…12 In this respect, compound ITH12246 could be considered as a wide spectrum neuroprotectant, a profile that is interesting taking into account the multifactorial nature of neurodegenerative diseases that, however, currently do not possess a huge battery of therapeutic strategies to slow down or counteract the disease. This is more dramatic in the case of AD, as there are no optimal medicines to treat AD patients, although the scientific community is tirelessly looking for new promising drugs and compromised targets, focusing mainly on the best-known physiopathological markers, that is Aβ 68 or aggregated τ protein, 69 as well as the so-called cholinergic hypothesis; 70 unfortunately, all of these approaches have failed. 71 As mentioned in the introduction section, stroke does not possess efficient medicines, too.…”

Section: ■ Conclusionmentioning

confidence: 99%

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

Lorrio

Romero

González‐Lafuente

et al. 2013

ACS Chem. Neurosci.

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ITH12246 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b] [1,8]naphthyridine-3-carboxylate) is a 1,8-naphthyridine described to feature an interesting neuroprotective profile in in vitro models of Alzheimer's disease. These effects were proposed to be due in part to a regulatory action on protein phosphatase 2A inhibition, as it prevented binding of its inhibitor okadaic acid. We decided to investigate the pharmacological properties of ITH12246, evaluating its ability to counteract the memory impairment evoked by scopolamine, a muscarinic antagonist described to promote memory loss, as well as to reduce the infarct volume in mice suffering phototrombosis. Prior to conducting these experiments, we confirmed its in vitro neuroprotective activity against both oxidative stress and Ca 2+ overload-derived excitotoxicity, using SH-SY5Y neuroblastoma cells and rat hippocampal slices. Using a predictive model of blood-brain barrier crossing, it seems that the passage of ITH12246 is not hindered. Its potential hepatotoxicity was observed only at very high concentrations, from 0.1 mM. ITH12246, at the concentration of 10 mg/kg i.p., was able to improve the memory index of mice treated with scopolamine, from 0.22 to 0.35, in a similar fashion to the well-known Alzheimer's disease drug galantamine 2.5 mg/kg. On the other hand, ITH12246, at the concentration of 2.5 mg/kg, reduced the phototrombosis-triggered infarct volume by 67%. In the same experimental conditions, 15 mg/kg melatonin, used as control standard, reduced the infarct volume by 30%. All of these findings allow us to consider ITH12246 as a new potential drug for the treatment of neurodegenerative diseases, which would act as a multifactorial neuroprotectant.

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Section: ■ Conclusionmentioning

confidence: 99%

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

Lorrio

Romero

González‐Lafuente

et al. 2013

ACS Chem. Neurosci.

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“…According to the docking results, EGCG had a tendency to associate with Aβ primarily near the hydrophilic N-terminus and the α-helical region spanning residues H13 to D23 (46). This binding pocket is near the H6, H13, and H14 residues that may be responsible for metal binding to Aβ, as well as to residues in the hydrophobic self-recognition sequence, suggested to be linked to Aβ aggregation pathways (1,3,8,(47)(48)(49). A combination of polar (e.g., hydrogen bonding, electrostatic interaction) and hydrophobic interactions was likely responsible for the close proximity of EGCG to hydrophilic and hydrophobic portions of Aβ in solution.…”

Section: Molecular Modeling Studies Present That Egcg Could Interact mentioning

confidence: 99%

Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

Hyung¹,

DeToma²,

Brender

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

211

260

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Despite the significance of Alzheimer's disease, the link between metal-associated amyloid-β (metal-Aβ) and disease etiology remains unclear. To elucidate this relationship, chemical tools capable of specifically targeting and modulating metal-Aβ species are necessary, along with a fundamental understanding of their mechanism at the molecular level. Herein, we investigated and compared the interactions and reactivities of the green tea extract, (−)-epigallocatechin-3-gallate [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate; EGCG], with metal [Cu(II) and Zn(II)]-Aβ and metal-free Aβ species. We found that EGCG interacted with metal-Aβ species and formed small, unstructured Aβ aggregates more noticeably than in metal-free conditions in vitro. In addition, upon incubation with EGCG, the toxicity presented by metalfree Aβ and metal-Aβ was mitigated in living cells. To understand this reactivity at the molecular level, structural insights were obtained by ion mobility-mass spectrometry (IM-MS), 2D NMR spectroscopy, and computational methods. These studies indicated that (i) EGCG was bound to Aβ monomers and dimers, generating more compact peptide conformations than those from EGCGuntreated Aβ species; and (ii) ternary EGCG-metal-Aβ complexes were produced. Thus, we demonstrate the distinct antiamyloidogenic reactivity of EGCG toward metal-Aβ species with a structurebased mechanism.amyloid-β peptide | metal ions | natural products | amyloidogenesis T he brain of individuals with Alzheimer's disease (AD) has protein aggregates composed of misfolded amyloid-β (Aβ) peptides (1-4). The Aβ peptides are produced endogenously through enzymatic cleavage of amyloid precursor protein. Aβ monomers can misfold and oligomerize into various intermediates before the formation and elongation of fibrils that exhibit a characteristic cross-β-sheet structure (1-4). The accumulation of aggregated Aβ species has been a key feature of the amyloid cascade hypothesis, which cites that these aggregates are possible causative agents in AD. In addition, transition metals, such as Cu and Zn, whose misregulation leads to aberrant neuronal function, have a suggested link to AD pathology (1,(3)(4)(5)(6)(7)(8). In vitro and in vivo studies have provided evidence for the direct interactions of metal ions with Aβ and their presence within Aβ plaques, indicating the formation of metal-associated Aβ (metal-Aβ) species. These metal-Aβ species have been implicated in processes that could lead to neurotoxicity (e.g., metal-induced Aβ aggregation and metal-Aβ-mediated reactive oxygen species generation) (1, 3-8). The involvement of metal-Aβ species in AD pathogenesis, however, has not been clearly elucidated. To advance our understanding of the potential neurotoxicity of metal-Aβ species, efforts to develop chemical tools capable of interacting directly with metal-Aβ species and modulating their reactivity in vitro and in biological systems are under way (1,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)...

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“…Metal coordination properties of Ab have been investigated employing a wide range of techniques such as nuclear magnetic resonance (NMR) spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, circular dichroism (CD) spectroscopy, and mass spectrometry (MS) (46)(47)(48). These studies have suggested that the coordination of Cu(II) and Zn(II) in Ab species could occur via three histidine residues (H6, H13, and H14) and possibly another N-terminal residue or the peptide backbone.…”

Section: Aluminiummentioning

confidence: 99%

Metal ions, Alzheimer's disease and chelation therapy

Budimir¹

2011

Acta Pharmaceutica

167

108

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Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, clinically characterized by memory and cognitive dysfunctions. It is primarily a disease of old age (1) and is the most prevalent cause of dementia in elderly people (2). AD affects about 35 million people worldwide today (3) and it is estimated to nearly double every 20 years, to reach 66 million in 2030, and 115 million in 2050 (3). There is no known cause and no cure for AD and these numbers makes finding a cure or rational treatment for AD an urgent priority. Despite significant advances in understanding the neuropathological and neurochemical events taking place in AD, the etiopathogenesis of progressive and mental cognitive dysfunction associated with aging remains largely unclear.Pathologically, AD is characterized by neuronal degeneration. The brains of AD patients are mainly characterized by extracellular proteic (or neuritic) deposits (amyloid or senile plaques) surrounded by dystrophic neuritic and intracellular neurofibrillary tangles (NFT) (4). The plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behavior such as the entorhinal cortex, hippocam- In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.

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The chemistry of Alzheimer’s disease

Abstract: The chemistry of Alzheimer's disease is largely centred on the amyloid beta-peptide, its formation, structure, and interactions with metals, membranes, proteins and other species. This critical review summarizes the current state of knowledge (252 references).

Cited by 393 publications

References 242 publications

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

Metal ions, Alzheimer's disease and chelation therapy

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