Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum
Abstract Amyloid-beta (Aβ) plaque formation in Alzheimer’s disease (AD) pathology is morphologically diverse. Understanding the association of polymorphic Aβ pathology with AD pathogenesis and progression is critical in light of emerging Aβ-targeting therapies. In this work, functional amyloid micro...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59085-7 |
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| author | Srinivas Koutarapu Junyue Ge Maciej Dulewicz Meera Srikrishna Alicja Szadziewska Jack Wood Kaj Blennow Henrik Zetterberg Wojciech Michno Natalie S. Ryan Tammaryn Lashley Jeffrey N. Savas Michael Schöll Jörg Hanrieder |
| author_facet | Srinivas Koutarapu Junyue Ge Maciej Dulewicz Meera Srikrishna Alicja Szadziewska Jack Wood Kaj Blennow Henrik Zetterberg Wojciech Michno Natalie S. Ryan Tammaryn Lashley Jeffrey N. Savas Michael Schöll Jörg Hanrieder |
| author_sort | Srinivas Koutarapu |
| collection | DOAJ |
| description | Abstract Amyloid-beta (Aβ) plaque formation in Alzheimer’s disease (AD) pathology is morphologically diverse. Understanding the association of polymorphic Aβ pathology with AD pathogenesis and progression is critical in light of emerging Aβ-targeting therapies. In this work, functional amyloid microscopy enhanced by deep learning was integrated with mass spectrometry imaging to delineate polymorphic plaques and to identify their associated Aβ make-up. In both sporadic AD (n = 12) and familial AD (n = 6), dense-core plaques showed higher levels of Aβ1-40 and N-terminal pyroglutamated Aβx-42 compared to diffuse plaques and plaques in non-demented, amyloid positive individuals (n = 5). Notably, a distinct dense-core plaque subtype, coarse-grained plaque, was observed in AD but not in non-demented, amyloid positive patients. Coarse-grained plaques were more abundant in early onset AD, showed increased neuritic dystrophy and higher levels of Aβ1-40 and Aβ3pE-40, an Aβ-pattern similar to cerebral amyloid angiopathy. The correlative chemical imaging paradigm presented here allowed to link structural and biochemical characteristics of Aβ plaque polymorphism across various AD etiologies. |
| format | Article |
| id | doaj-art-3d44e5a2512d4b7eabd6860dd091567c |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3d44e5a2512d4b7eabd6860dd091567c2025-08-20T02:30:24ZengNature PortfolioNature Communications2041-17232025-04-0116111910.1038/s41467-025-59085-7Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrumSrinivas Koutarapu0Junyue Ge1Maciej Dulewicz2Meera Srikrishna3Alicja Szadziewska4Jack Wood5Kaj Blennow6Henrik Zetterberg7Wojciech Michno8Natalie S. Ryan9Tammaryn Lashley10Jeffrey N. Savas11Michael Schöll12Jörg Hanrieder13Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgUK Dementia Research Institute, University College LondonDepartment of Neurodegenerative Disease, Queen Square Institute of Neurology, University College LondonKen and Ruth Davee Department of Neurology, Northwestern University Feinberg School of MedicineDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgDepartment of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of GothenburgAbstract Amyloid-beta (Aβ) plaque formation in Alzheimer’s disease (AD) pathology is morphologically diverse. Understanding the association of polymorphic Aβ pathology with AD pathogenesis and progression is critical in light of emerging Aβ-targeting therapies. In this work, functional amyloid microscopy enhanced by deep learning was integrated with mass spectrometry imaging to delineate polymorphic plaques and to identify their associated Aβ make-up. In both sporadic AD (n = 12) and familial AD (n = 6), dense-core plaques showed higher levels of Aβ1-40 and N-terminal pyroglutamated Aβx-42 compared to diffuse plaques and plaques in non-demented, amyloid positive individuals (n = 5). Notably, a distinct dense-core plaque subtype, coarse-grained plaque, was observed in AD but not in non-demented, amyloid positive patients. Coarse-grained plaques were more abundant in early onset AD, showed increased neuritic dystrophy and higher levels of Aβ1-40 and Aβ3pE-40, an Aβ-pattern similar to cerebral amyloid angiopathy. The correlative chemical imaging paradigm presented here allowed to link structural and biochemical characteristics of Aβ plaque polymorphism across various AD etiologies.https://doi.org/10.1038/s41467-025-59085-7 |
| spellingShingle | Srinivas Koutarapu Junyue Ge Maciej Dulewicz Meera Srikrishna Alicja Szadziewska Jack Wood Kaj Blennow Henrik Zetterberg Wojciech Michno Natalie S. Ryan Tammaryn Lashley Jeffrey N. Savas Michael Schöll Jörg Hanrieder Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum Nature Communications |
| title | Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum |
| title_full | Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum |
| title_fullStr | Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum |
| title_full_unstemmed | Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum |
| title_short | Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum |
| title_sort | chemical imaging delineates aβ plaque polymorphism across the alzheimer s disease spectrum |
| url | https://doi.org/10.1038/s41467-025-59085-7 |
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