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Chemical imaging of evolving amyloid plaque pathology and associated A beta peptide aggregation in a transgenic mouse model of Alzheimer's disease
Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Molndal, Sweden.ORCID iD: 0000-0002-3096-3604
Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Molndal, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0002-9430-3859
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(English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159Article in journal (Refereed) Epub ahead of print
Abstract [en]

One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid beta (A beta) plaques. While A beta has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular A beta plaque pathology manifests itself upon aggregation of distinct A beta peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the A beta aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what A beta species aggregate and form plaques remains unclear. The aim of this study was to investigate the potential of matrix-assisted laser desorption/ionization imaging mass spectrometry as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality - matrix-assisted laser desorption/ionization imaging mass spectrometry - that allows for delineating A beta aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid-long A beta (A beta 1-42). Plaque maturation was found to be characterized by a relative increase in deposition of A beta 1-40, which was associated with the appearance of a cored morphology for those plaques. Finally, other C-terminally truncated A beta species (A beta 1-38 and A beta 1-39) exhibited a similar aggregation pattern as A beta 1-40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by A beta 1-42; a process that is followed by plaque maturation upon deposition of A beta 1-40 as well as deposition of other C-terminally modified A beta species.

Place, publisher, year, edition, pages
WILEY.
Keywords [en]
Alzheimer's disease, beta-amyloid, MALDI imaging, plaque pathology, transgenics
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-397798DOI: 10.1111/jnc.14888ISI: 000494419200001PubMedID: 31605538OAI: oai:DiVA.org:uu-397798DiVA, id: diva2:1373365
Funder
Swedish Research Council, 2014-6447Swedish Research Council, 2018-02532Swedish Research Council, 2017-00915Swedish Research Council, 2017-02413Swedish Research Council, 2018-02715Swedish Research Council, 2018-02181Knut and Alice Wallenberg FoundationEU, European Research Council, 681712The Swedish Brain FoundationÅke Wiberg FoundationStiftelsen Gamla TjänarinnorGun och Bertil Stohnes StiftelseTorsten Söderbergs stiftelseThe Dementia Association - The National Association for the Rights of the DementedAvailable from: 2019-11-27 Created: 2019-11-27 Last updated: 2020-02-17Bibliographically approved

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Meier, Silvio R.Sehlin, DagSyvänen, Stina

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