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Abstract
Alzheimer's disease (AD) is characterised by the formation of amyloid deposits composed primarily of the amyloid β-peptide (Aβ). This peptide has been shown to bind redox active metals ions such as copper and iron, leading to the production of reactive oxygen species (ROS) and formation of hydrogen peroxide (H2O2). The generation of H2O2 has been linked with Aβ neurotoxicity and neurodegeneration in AD. Because of the relative stability of a tyrosyl radical, the tyrosine residue (Tyr-10) is believed to be critical to the neurotoxicity of Aβ. This residue has also been shown to be important to Aβ aggregation and amyloid formation. It is possible that the formation of an Aβ tyrosyl radical leads to increased aggregation via the formation of dityrosine as an early aggregation step, which is supported by the identification of dityrosine in amyloid plaque. The role of dityrosine formation in Aβ aggregation and neurotoxicity is as yet undetermined, partly because there are no facile methods for the synthesis of Aβ dimers containing dityrosine. Here we report the use of horseradish peroxidase and H2O2 to dimerise N-acetyl-l-tyrosine ethyl ester and apply the optimised conditions for dityrosine formation to fully unprotected Aβ peptides. We also report a simple fluorescent plate reader method for monitoring Aβ dimerisation via dityrosine formation.
| Abbreviations | ||
| ATEE | = | N-acetyl tyrosyl ethyl ester |
| AD | = | Alzheimer's disease |
| Aβ | = | Amyloid β peptide |
| APP | = | β amyloid precursor protein |
| Boc | = | t-Butyloxycarbonyl |
| DOPA | = | 3, 4-dihydroxyphenylalanine |
| ECL | = | enhanced chemiluminescence |
| ESI-MS | = | Electrospray-ionization mass spectrometry |
| HFIP | = | hexafluoroisopropanol |
| MCA | = | multichannel analysis mode |
| MCO | = | Metal catalysed oxidation |
| NFT | = | intracellular neurofibrilar tangles |
| OH | = | hydroxyl radical |
| PBS | = | Phosphate buffered saline |
| ROS | = | Reactive oxygen species |
| RP-HPLC | = | Reversed phase-high performance liquid chromatography |
| SDS | = | sodium dodecyl sulphate |
| TR | = | Tyrosyl radical |
| Abbreviations | ||
| ATEE | = | N-acetyl tyrosyl ethyl ester |
| AD | = | Alzheimer's disease |
| Aβ | = | Amyloid β peptide |
| APP | = | β amyloid precursor protein |
| Boc | = | t-Butyloxycarbonyl |
| DOPA | = | 3, 4-dihydroxyphenylalanine |
| ECL | = | enhanced chemiluminescence |
| ESI-MS | = | Electrospray-ionization mass spectrometry |
| HFIP | = | hexafluoroisopropanol |
| MCA | = | multichannel analysis mode |
| MCO | = | Metal catalysed oxidation |
| NFT | = | intracellular neurofibrilar tangles |
| OH | = | hydroxyl radical |
| PBS | = | Phosphate buffered saline |
| ROS | = | Reactive oxygen species |
| RP-HPLC | = | Reversed phase-high performance liquid chromatography |
| SDS | = | sodium dodecyl sulphate |
| TR | = | Tyrosyl radical |