X-Ray absorption spectroscopy, nuclear magnetic resonance spectroscopy, and together quantum mechanics calculations could help researchers pin down the role of metal ions in the formation of the beta-amyloid plaques present in Alzheimer's disease.
More than twenty diseases, including Alzheimer's disease, involve the production of errant forms of various natural proteins and peptides in the brain and other tissues. The process of amyloidosis in which these peptides and proteins switch from a physiological soluble configuration to an insoluble and pathological has been well studied. It is well known that amyloidosis leads to the formation of harmful plaques.
However, while plaques are known to contain fairly high concentrations of transition metal elements, including copper, iron, and zinc, the role of these metals in plaque formation is not yet fully understood. Indeed, the presence of such metals at higher than normal levels may be a cause or an effect. New evidence from the use of metal-grabbing chelating agents, which have been found to solubilize amyloid aggregates would suggest the former, particular with regards copper and zinc in Alzheimer's disease. Such a finding points to possible new treatments for this disease but also raises new questions about the precise role of metal ions in plaque formation.
Now, Velia Minicozzi, Sylvia Morante, Gian Carlo Rossi, and Francesco Stellato of the Department of Physics at the University of Rome Tor Vergata, Italy, Nils Christian of Humboldt University, in Berlin, and Karl Jansen of NIC DESY-Zeuthen, Germany, have used a raft of analytical techniques together with quantum mechanics to turn a spotlight on this role.
The main protein-like component present in the amyloid plaques found in the brains of patients with Alzheimer's disease is the beta-amyloid peptide. This material originates from the splitting of Amyloid Precursor Protein (APP), which itself is a 770 amino acid transmembrane protein coded by chromosome 21. The researchers point out that there are several so-called secretase enzymes that can cleave APP. When two secretases work together harmless cleavage products are formed. However, an alternative cleavage pathway results in the harmful form of the protein.
The researchers add that recent experimental evidence suggests that these peptides can complex with both copper and zinc ions, and there are hints that these two metals play counteractive roles, with copper inhibiting the tendency of zinc to induce protein aggregation. Of course, both copper and zinc are essential to several metabolic processes in the brain and elsewhere in the body, so excluding them is not an option.
However, these metals must be present in specific forms to function and not to trigger pathological effects. Copper, iron, and zinc are all present at fairly high concentrations in the healthy brain and evidence suggests that the breakdown of regulation of metal trafficking across the blood-brain barrier is associated with age-related neurodegenerative diseases. Other researchers have hinted that copper and zinc may lead to the precipitation process that forms amyloid plaques.
The German-Italian team have used modern spectroscopic techniques and numerical first principle simulations to investigate the physicochemical basis of such amyloid aggregation. Specifically, they turned to X-ray absorption spectroscopy to successfully reveal the atomic structure around the metal binding sites in amyloid peptides complexed with either copper or zinc ions. NMR spectroscopic information then showed them the amino acid residues that are coordinated to the metals.
The experiments with copper show that three histidine residues in the protein sequence are involved, whereas zinc coordination apparently involves four histidines. This, the team explains, suggests that zinc is somehow involved in promoting the aggregation of amyloid sequences into fibrous plaques.
In order to find a theoretical basis for this assertion, the team turned to first principle ab initio molecular dynamics simulations, which they found fitted nicely with the NMR and X-ray data. "Although we are still far from a clear understanding of the role of metals in protein misfolding and/or aggregation, experimental and theoretical studies, not unexpectedly, seem to point to a rather complicated structural scenario," the researchers say. http://www.spectroscopynow.com
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posted by Valery Yermalitsky at
7:03 AM
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