Abstract
Alzheimer's disease (AD) is the most common form of dementia among older people. Although the etiology of AD is still poorly understood, the pathology is known and has been caracterized for over 100 years since Alois Alzheimer first described "a peculiar disease of cerebral cortex".Despite tremendous research efforts, current treatment as well as diagnostic options for AD are limited, consequently there is a need for the development of new effective therapies and biomarkers for the earlier detection in vivo of this disease.
The mounting evidence supporting the role(s) of metal ions in the pathology of AD has rendered metal-ion chelation therapy a promising treatment strategy. Appropiate chelators can be designed to potentially disrupt amyloid-beta (Ab) pathology.
Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules, which contain both amyloid-binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework, include potential antioxidant properties, facilitate iodine-labelled derivatives and can be permeable through the blood-brain barrier. The chelating properties of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT) and 2-(2-aminophenyl)-1H-benzimidazole (BM), and corresponding iodinated derivatives, HBXI, HBTI and BMI, towards copper(II) and zinc(II) have been examined in the solid phase and in solution. The calculated stability constants for the ML2 complexes evidence that HBXI, HBTI and BMI can be efficient chelators for sequestering the Cu(II) and Zn(II) metal ions that are present in soluble Ab peptide forms, and this result was also confirmed by Ab aggregation turbidimetry assays, especially in the case of Cu(II). Finally, the fluorescence measurements on HBX, HBT, BM and corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pre-grown fibrils, have shown that HBX and HBT compounds could behave as potential markers for the presence of amyloid fibrils whereas HBXI and HBTI may be especially suitable for radioisotopic detection of Ab deposits. Overall, these preliminary findings are evidence of the potential of thioflavin-based intercalation compounds with integrated metal chelating properties as candidates for targeting Alzheimer's amyloidogenesis. Studies on the understanding of the binding of the ThT+ cation to amyloid fibrils and on the suitability of the above compounds to cross the BBB in transgenic mice are now in progress.
| Date of Award | 4 Sept 2010 |
|---|---|
| Original language | Catalan |
| Supervisor | Pilar González Duarte (Director) |