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Role and Control of Metal-Mediated Fibril Toxicity
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David Allsop and Ashley Bush led this live discussion on 20 December 2004. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
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 View Transcript of Live Discussion — Posted 22 August 2006
Background Text
We thank Bentham Science Publishers, Ltd. for providing the full text of reviews from David Allsop's (Tabner et al., 2003) and Ashley Bush's labs (Curtain et al., 2003) that serve as background for this live discussion, which is part of an ongoing series spurred by the recent special issue of Current Medicinal Chemistry-Immunology, Endocrine & Metabolic Agents on misfolded protein in disease.
See Allsop Full Text (.pdf)
See Bush Full Text (.pdf)
Introduction
Evidence for the role of metals in the toxicity of fibrillogenic proteins has grown dramatically over the last decade or so. While dietary aluminum was once touted as a potential risk factor for Alzheimer disease (a theory that still has support, see our hypothesis pages for a new twist to the aluminum debate), there is now much better evidence linking endogenous copper, iron, and zinc with the biochemistry and toxicity of amyloid-β (Aβ) and other fibrillogenic peptides, including α-synuclein. Work from Ashley Bush's lab at Massachusetts General Hospital has shown that Aβ1-42 binds Cu(II) with extremely high affinity (attomolar dissociation constant), and that completely removing the metal from solution prevents aggregation of Aβ (see Atwood et al., 2000). Similarly, Dave Schubert at the Salk Institute, together with Mordechai Chevion at the Hebrew University, has shown that iron is required for the toxicity of Aβ (Schubert and Chevion, 1995). Zinc has also been shown to precipitate aggregation of Aβ (see Bush et al., 1994). Such observations are not limited to in vitro experiments. Larry Sparks at the Sun Health Research Institute recently reported that minute amounts of copper in the drinking water can induce aggregation of Aβ in rabbit brain (see Sparks et al., 2003 and ARF related news story), while the absence of synaptic zinc in mice expressing human AβPP carrying the Swedish mutations has been correlated with reduced plaque load (see Lee et al., 2002 and ARF related news story).
How do transition metals affect Aβ biochemistry and toxicity? Do they simply provide some additional glue to keep Aβ fibrils together, or do they have a more sinister role? What about redox chemistry? Though zinc has little or no redox activity, both ferric [Fe(II)] and cupric ions [Cu(I)] can take part in the Fenton reaction, the reduction of hydrogen peroxide to hydroxyl ion and hydroxyl radical. The latter is extremely reactive and can oxidize macromolecules at rates that are comparable to diffusion speeds. In other words, hydroxyl radicals are formed and wreak havoc in an instant. Could fibrils somehow catalyze the Fenton reaction?
At Bush's lab, Xudong Huang used a chemical assay to reveal that Aβ, in the presence of Fe(III), produces hydrogen peroxide (see Huang et al., 1999), one of the Fenton ingredients. This was confirmed in David Allsop's lab by use of electron spin resonance spectroscopy (see Turnbull et al., 2001). In these experiments, Allsop's group was able to demonstrate that toxicity and production of hydrogen peroxide go hand in hand. Aβ1-42 and Aβ25-35, for example, are neurotoxic and peroxide generators, whereas AA1-15 (a fragment of the Amyloid A protein) is neither even though it aggregates. Allsop’s group has also found that α-synuclein and certain toxic forms of the prion protein also generate peroxide (see Turnbull et al. 2003 and Turnbull et al. 2003 ), suggesting that there may be a toxic mechanism common to all these fibrillogenic proteins. Cu(II) can also contribute to production of hydrogen peroxide by Aβ, but because zinc does not, it has been suggested that formation of Aβ-Zn aggregates may offer some rudimentary protection against the Aβ toxicity (see Lovell et al., 1998). All told, the evidence points to iron- or copper-mediated production of hydrogen peroxide by Aβ, followed perhaps by Fenton chemistry to produce hydroxyl radicals.
These findings are also suggestive of a therapeutic intervention-metal chelation. Bush has pioneered the use of clioquinol, which was originally developed as an antibiotic, but which also acts as a metal chelator. It is much superior to common chelators such as EDTA (ethylenediamine tetraacetic acid) because it is small and hydrophobic, and readily crosses the blood-brain barrier. In fact, recent work from Bush's lab has shown that clioquinol can substantially reduce the plaque load in APP2576 transgenic mice (Cherny et al., 2001; see also ARF related news story). It has also been shown to protect mice in an experimental model of Parkinson disease (see Kaur et al., 2003 and ARF related news story). The drug is currently in clinical trials (see our clinical trial data page).
In this live discussion, we will debate the current theories and developments pertaining to metal-related biochemistry and neurodegenerative disease, including, but not limited to:
- Exactly what forms of aggregates produce ROS?
- Is aggregation-mediated ROS production widespread, or limited to just a few proteins, such as Aβ, α-synuclein, and prions?
- How can the impact of redox and non-redox metals on sporadic neurodegenerative diseases be quantitated?
- Why are only certain neurons affected?
- Production of hydrogen peroxide by Aβ, and Aβ toxicity—coincidence, or cause and effect?
- Why is clioquinol, a relatively weak chelator, so effective in animal models? Is it due to a specific interaction with Aβ, and if so, can this information be used to develop more potent compounds?
We thank David Allsop and Ashley Bush for jointly leading this discussion, and we encourage you to read their recent reviews (see Background text above).—Tom Fagan.
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