Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation
The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003772 |
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| author | Hiroto Nakano Sadao Hikishima Makoto Mori Jota Minamikawa Daiki Muramatsu Yasuhiro Sakashita Tokuhei Ikeda Moeko Noguchi-Shinohara David B. Teplow Kenjiro Ono |
| author_facet | Hiroto Nakano Sadao Hikishima Makoto Mori Jota Minamikawa Daiki Muramatsu Yasuhiro Sakashita Tokuhei Ikeda Moeko Noguchi-Shinohara David B. Teplow Kenjiro Ono |
| author_sort | Hiroto Nakano |
| collection | DOAJ |
| description | The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However, the precise mechanisms of their molecular functions within the Aβ aggregation cascade have not been clarified so far. This research aimed to uncover the structural and functional characteristics of globular-shaped Aβ oligomers (gAβO) under in vitro conditions. We performed thioflavin T (ThT) assays on low-molecular-weight (LMW) Aβ42, testing different concentrations of Aβ42 mature fibril (MF) seeds and gAβO. Fibril formation was continuously observed using high-speed atomic force microscopy (HS-AFM) in LMW Aβ42 with different sample conditions. Conformational changes of Aβ42 aggregates in the presence of gAβO was also evaluated using circular dichroism spectroscopy. The results of the ThT analysis and HS-AFM observation indicated that gAβO promoted fibril formation of LMW Aβ42 while gAβO itself did not form fibrous aggregates, indicating that gAβO would have a catalytic effects on LMW Aβ42 aggregation. We also showed that the molecular interaction of gAβO was altered by the presence and amount of MF seeds in the reaction buffers, indicating that complex interactions would exist among different Aβ species. The results of our present research demonstrated that gAβO would have significant roles to accelerate Aβ aggregation in AD pathogenesis.225 < 250 words. |
| format | Article |
| id | doaj-art-5f616895d22543638fcbac13c5baf8c8 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-5f616895d22543638fcbac13c5baf8c82025-01-24T04:44:37ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106775Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongationHiroto Nakano0Sadao Hikishima1Makoto Mori2Jota Minamikawa3Daiki Muramatsu4Yasuhiro Sakashita5Tokuhei Ikeda6Moeko Noguchi-Shinohara7David B. Teplow8Kenjiro Ono9Department of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, JapanDepartment of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, JapanDepartment of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, JapanDepartment of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, JapanDepartment of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, JapanDepartment of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, JapanDepartment of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, JapanDepartment of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, JapanDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7334, United StatesDepartment of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1, Kanazawa 920-8640, Japan; Corresponding author.The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However, the precise mechanisms of their molecular functions within the Aβ aggregation cascade have not been clarified so far. This research aimed to uncover the structural and functional characteristics of globular-shaped Aβ oligomers (gAβO) under in vitro conditions. We performed thioflavin T (ThT) assays on low-molecular-weight (LMW) Aβ42, testing different concentrations of Aβ42 mature fibril (MF) seeds and gAβO. Fibril formation was continuously observed using high-speed atomic force microscopy (HS-AFM) in LMW Aβ42 with different sample conditions. Conformational changes of Aβ42 aggregates in the presence of gAβO was also evaluated using circular dichroism spectroscopy. The results of the ThT analysis and HS-AFM observation indicated that gAβO promoted fibril formation of LMW Aβ42 while gAβO itself did not form fibrous aggregates, indicating that gAβO would have a catalytic effects on LMW Aβ42 aggregation. We also showed that the molecular interaction of gAβO was altered by the presence and amount of MF seeds in the reaction buffers, indicating that complex interactions would exist among different Aβ species. The results of our present research demonstrated that gAβO would have significant roles to accelerate Aβ aggregation in AD pathogenesis.225 < 250 words.http://www.sciencedirect.com/science/article/pii/S0969996124003772Alzheimer's diseaseAβGlobular-shaped Aβ oligomerHigh-molecular-weight Aβ oligomerHigh-speed atomic force microscopy |
| spellingShingle | Hiroto Nakano Sadao Hikishima Makoto Mori Jota Minamikawa Daiki Muramatsu Yasuhiro Sakashita Tokuhei Ikeda Moeko Noguchi-Shinohara David B. Teplow Kenjiro Ono Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation Neurobiology of Disease Alzheimer's disease Aβ Globular-shaped Aβ oligomer High-molecular-weight Aβ oligomer High-speed atomic force microscopy |
| title | Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation |
| title_full | Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation |
| title_fullStr | Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation |
| title_full_unstemmed | Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation |
| title_short | Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation |
| title_sort | globular shaped aβ oligomers have diverse mechanisms for promoting aβ aggregations with the facilitation of fibril elongation |
| topic | Alzheimer's disease Aβ Globular-shaped Aβ oligomer High-molecular-weight Aβ oligomer High-speed atomic force microscopy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003772 |
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