Alzheimer's disease, metal ions and metal homeostatic therapy

Zatta, Paolo; Drago, Denise; Bolognin, Silvia; Sensi, Stefano L.

doi:10.1016/j.tips.2009.05.002

Cited by 325 publications

(270 citation statements)

References 111 publications

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“…This proposal is also in line of very recent attempts to control copper levels in the body -an 'anti-copper campaign' -suspected to be involved (among others) in neuro-degenerative diseases (e.g. Zatta et al 2009). The proposed system warrants further studies.…”

Section: Other Commentssupporting

confidence: 70%

Predicted intake of trace elements and minerals via household drinking water by 6-year-old children from Krakow, Poland. Part 5: Zinc

Bartoń

2010

Food Additives & Contaminants: Part A

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Section: Other Commentssupporting

confidence: 70%

Predicted intake of trace elements and minerals via household drinking water by 6-year-old children from Krakow, Poland. Part 5: Zinc

Bartoń

2010

Food Additives & Contaminants: Part A

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“…However, there has been a growing interest in a number of pharmacological ap-proaches to help slow down the rate of both cognitive and functional declines associated with aging while maintaining a positive quality of life. One of the currently accepted hypotheses, the metal hypothesis of Alzheimer's disease states that the interactions between metal ions and Ab, as well as abnormal metal ion homeostasis, are connected with AD neuropathogenesis (49)(50)(51). Based on this hypothesis, disruption of metal-Ab interactions via metal chelation therapy has been proposed in order to reduce neurotoxicity of metal-Ab species and restore metal ion homeostasis in the brain (52).…”

Section: Metals Chelators For the Treatment Of Alzheimer's Diseasementioning

confidence: 99%

Metal ions, Alzheimer's disease and chelation therapy

Budimir¹

2011

Acta Pharmaceutica

179

113

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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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“…In addition to Aβ aggregate deposits, dyshomeostasis and miscompartmentalization of metal ions such as Fe, Cu, and Zn ions clearly occur in AD brains (1)(2)(3)(4)(6)(7)(8)(9)(10). Some studies suggest that highly concentrated metal ions play an important role in Aβ aggregate deposition and neurotoxicity including the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) (1-4, 6-13).…”

mentioning

confidence: 99%

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi

Braymer

Nanga

et al. 2010

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

256

420

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The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N 1 ,N 1 -dimethyl-N 4 -(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.amyloid-β peptide | copper | zinc | reactive oxygen species | rational structure-based design M ore than 24 million people worldwide have Alzheimer's disease (AD), a devastating and fatal form of dementia (1-3). The key pathological markers in AD are amyloid-β (Aβ) plaques and neurofibrillary tangles, the accumulation of which is accompanied by oxidative stress, inflammation, and neurodegeneration. The "amyloid hypothesis" in AD states that Aβ, generated via cleavage of the amyloid precursor protein (APP) by β-and γ-secretases, is a proximal causative agent (1-4). It is, however, still unclear which morphological Aβ species, from soluble small oligomers to large fibrils, are central to AD pathogenesis (1-5).In addition to Aβ aggregate deposits, dyshomeostasis and miscompartmentalization of metal ions such as Fe, Cu, and Zn ions clearly occur in AD brains (1-4, 6-10). Some studies suggest that highly concentrated metal ions play an important role in Aβ aggregate deposition and neurotoxicity including the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) (1-4, 6-13). The role of metal ions in AD and molecular mechanisms of metal-Aβ-associated pathological pathways, however, are not fully understood. Using traditional metal chelating agents, potential regulation of metal-induced Aβ aggregation and neurotoxicity has been shown in vitro and in vivo (1-4, 6, 10, 13-17). Some compounds such as clioquinol (CQ) and an 8-hydroxyquinoline derivative (PBT2) have moved into clinical trials and showed improved cognition. Long-term use of CQ is, however, limited by an adverse side effect, subacute myelo-optic neuropathy (18). Although these traditional metal chelators have yet to be available as therapeutic agents, the studies using these compounds show the possible involvement of metal ions in AD pathogenesis.To elucidate the pathological ...

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Alzheimer's disease, metal ions and metal homeostatic therapy

Cited by 325 publications

References 111 publications

Predicted intake of trace elements and minerals via household drinking water by 6-year-old children from Krakow, Poland. Part 5: Zinc

Predicted intake of trace elements and minerals via household drinking water by 6-year-old children from Krakow, Poland. Part 5: Zinc

Metal ions, Alzheimer's disease and chelation therapy

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

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