Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues

Everett, James; Brooks, Jake; Tjendana Tjhin, Vindy; Lermyte, Frederik; Hands-Portman, Ian; Plascencia-Villa, Germán; Perry, George; Sadler, Peter J.; O’Connor, Peter B.; Collingwood, Joanna F.; Telling, Neil D.

doi:10.1021/acschemneuro.3c00756

Title: Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues

Journal Article · 19 March 2024 · ACS Chemical Neuroscience

DOI: https://doi.org/10.1021/acschemneuro.3c00756 · OSTI ID:2471005

^[1]; Brooks, Jake ^[2];

^[2]; Lermyte, Frederik ^[3]; Hands-Portman, Ian ^[2]; Plascencia-Villa, Germán ^[4];

^[4];

^[2];

^[5]

Keele University (United Kingdom); Univ. of Warwick, Coventry (United Kingdom)
Univ. of Warwick, Coventry (United Kingdom)
Univ. of Warwick, Coventry (United Kingdom); Technical Univ. of Darmstadt (Germany)
Univ. of Texas at San Antonio, TX (United States)
Keele University (United Kingdom)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2471005

Journal Information:: ACS Chemical Neuroscience, Journal Name: ACS Chemical Neuroscience Journal Issue: 7 Vol. 15; ISSN 1948-7193

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis? Wang, Feixue; Wang, Jiandong; Shen, Ying Frontiers in Aging Neuroscience, Vol. 14 https://doi.org/10.3389/fnagi.2022.830569	journal	March 2022
New Insights Into the Pathogenesis of Alzheimer's Disease Fan, Liyuan; Mao, Chengyuan; Hu, Xinchao Frontiers in Neurology, Vol. 10 https://doi.org/10.3389/fneur.2019.01312	journal	January 2020
The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light Collingwood, Joanna F.; Davidson, Mark R. Frontiers in Pharmacology, Vol. 5 https://doi.org/10.3389/fphar.2014.00191	journal	August 2014
Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer’s Disease Aaseth, Jan; Skalny, Anatoly V.; Roos, Per M. International Journal of Molecular Sciences, Vol. 22, Issue 17 https://doi.org/10.3390/ijms22179461	journal	August 2021
Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer’s Disease? Di Natale, Giuseppe; Sabatino, Giuseppina; Sciacca, Michele Francesco Maria Molecules, Vol. 27, Issue 16 https://doi.org/10.3390/molecules27165066	journal	August 2022
Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration Sánchez-Alcázar, JoséA; Villalón-García, Irene; Povea-Cabello, Suleva Neural Regeneration Research, Vol. 18, Issue 6 https://doi.org/10.4103/1673-5374.358614	journal	January 2023

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