| Autor: |
Everett J; School of Pharmacy and Bioengineering, Guy Hilton Research Centre, Keele University, Thornburrow Drive,Stoke-on-Trent,Staffordshire ST4 7QB, U.K.; School of Engineering, University of Warwick, Library Road,Coventry CV4 7AL, U.K., Brooks J; School of Engineering, University of Warwick, Library Road,Coventry CV4 7AL, U.K., Tjendana Tjhin V; School of Engineering, University of Warwick, Library Road,Coventry CV4 7AL, U.K., Lermyte F; School of Engineering, University of Warwick, Library Road,Coventry CV4 7AL, U.K.; Department of Chemistry, Technical University of Darmstadt, Alarich-Weiss-Strasse 4, 64287 Darmstadt, Germany., Hands-Portman I; School of Life Sciences, University of Warwick, Gibbet Hill Campus,Coventry CV4 7AL, U.K., Plascencia-Villa G; Department of Developmental and Regenerative Biology, The University of Texas at San Antonio (UTSA), San Antonio, Texas 78249, United States., Perry G; Department of Developmental and Regenerative Biology, The University of Texas at San Antonio (UTSA), San Antonio, Texas 78249, United States., Sadler PJ; Department of Chemistry, University of Warwick, Library Road,Coventry CV4 7AL, U.K., O'Connor PB; Department of Chemistry, University of Warwick, Library Road,Coventry CV4 7AL, U.K., Collingwood JF; School of Engineering, University of Warwick, Library Road,Coventry CV4 7AL, U.K., Telling ND; School of Pharmacy and Bioengineering, Guy Hilton Research Centre, Keele University, Thornburrow Drive,Stoke-on-Trent,Staffordshire ST4 7QB, U.K. |
| Abstrakt: |
The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer's disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C-H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer's brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer's disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer's disease. |
