Title: X-ray Absorption Spectroscopy in Understanding and Treating Alzheimer's Disease
Speaker: Dr. Kelly Summers (Johns Hopkins University)
Abstract: Although Alzheimer’s disease (AD) was first described over a century ago, it remains the leading cause of age-related dementia, and there is no cure. Innumerable changes in the brain have been linked to the pathology of AD, including aggregation of the amyloid beta (Aβ) peptide, and colocalized deposition of iron, copper, and zinc in the brain. To correct the metal ion imbalance and solubilize Aβ, metal chelation therapy has been explored as a possible AD treatment. Promising results with 8-hydroxyquinoline (8HQ)-based chelators showed improvements in both cognition and memory in pre-clinical studies and clinical trials. To further explore the mechanism of action of 8HQ chelators, we investigated the solution structure of 8HQ copper complexes, as well as the copper(II) binding site in Aβ, using both X-ray absorption spectroscopy (XAS) and high energy resolution fluorescence detected (HERFD) XAS. We found that Aβ binds Cu(II) in several different conformations that depend on pH and other solution conditions.1 We found that PBT2 binds copper differently than other 8HQs, with several different Cu(II) complexes possible with PBT2.2, 3 Using X-ray fluorescence imaging, we also found that PBT2 treatment results in altered intracellular copper accumulation compared to treatment with other 8HQs.4 Taking these results together, we propose that the observed differences in Cu(II) binding between the various 8HQs investigated may be key to controlling in vivo interactions with aggregated brain Aβ, which could
have significant implications for the development of future disease treatments.
Recommended Reading
1. Summers, K. L., Schilling, K. M., Roseman, G., Markham, K. A., Dolgova, N. V., Kroll, T., Sokaras, D., Millhauser, G. L., Pickering, I. J., and George, G. N. (2019) X-ray absorption spectroscopy investigations of copper(II) coordination in the human amyloid β peptide, Inorg. Chem. 58(9):
6294-6311. [ Ссылка ]
2. Summers, K. L., Pushie, M. J., Sopasis, G. J., James, A. K., Dolgova, N. V., Kroll, T., Sokaras, D., Harris, H. H., Pickering, I. J., and George, G. N. (2020) Solution chemistry of copper(II) binding to 8-hydroxyquinolines, Inorg. Chem. 59(19): 13858–13874. [ Ссылка ]
3. Summers, K. L., Roseman, G., Sopasis, G. J., Millhauser, G. L., Harris, H. H., Pickering, I. J., and George, G. N. (2020) Copper(II) binding to PBT2 differs from other 8-hydroxyquinoline chelators: Implications for the treatment of neurodegenerative protein misfolding diseases, Inorg. Chem.
59(23): 17519–17534. [ Ссылка ]
4. Summers, K. L., Dolgova N. V., Gagnon, K. B., Sopasis, G. J., James, A. K., Lai, B., Sylvain, N. J., Harris, H. H., Nichol, H. K., George, G. N., Pickering, I. J. (2020) PBT2 acts through a different mechanism of action than other 8-hydroxyquinolines: An X-ray fluorescence imaging study. Metallomics. 12(12): 1979-1994. [ Ссылка ]
