Impact of tyrosine amination on the aggregation and neurotoxicity of amyloid-β
(2025) In International Journal of Biological Macromolecules 306.- Abstract
The tyrosine residue in amyloid-β (Aβ) is susceptible to attack by various reactive nitrogen intermediates, leading to the formation of 3-nitrotyrosine (3-NT), a post-translational modification associated with the pathophysiology of Alzheimer's disease (AD). Although considered a “dead-end” product, emerging evidence suggests that 3-NT can be reduced to 3-aminotyrosine (3-AT) in vivo. This study aims to validate the amination of Aβ tyrosine under physiological conditions and systematically investigate its impact on the aggregation and neurotoxicity of Aβ42. Our investigations reveal that tyrosine amination mitigates the highly ordered β-structure content of Aβ42, thereby modulating its aggregation pathway, which is primarily dominated... (More)
The tyrosine residue in amyloid-β (Aβ) is susceptible to attack by various reactive nitrogen intermediates, leading to the formation of 3-nitrotyrosine (3-NT), a post-translational modification associated with the pathophysiology of Alzheimer's disease (AD). Although considered a “dead-end” product, emerging evidence suggests that 3-NT can be reduced to 3-aminotyrosine (3-AT) in vivo. This study aims to validate the amination of Aβ tyrosine under physiological conditions and systematically investigate its impact on the aggregation and neurotoxicity of Aβ42. Our investigations reveal that tyrosine amination mitigates the highly ordered β-structure content of Aβ42, thereby modulating its aggregation pathway, which is primarily dominated by the multi-step secondary nucleation. Aminotyrosine fibrils exhibit enhanced fragmentation, increasing fibril elongation rate, and insoluble aggregate production. Concurrently, tyrosine amination attenuates the neurotoxicity of Aβ42 by reducing intracellular reactive oxygen species (ROS) production and mitigating cell membrane disruption. Tyrosine amination substantially alters the aggregation and physiological properties of Aβ42. Nitration of Aβ42 and subsequent conversion to tyrosine-aminated Aβ42 may represent an intrinsic defensive response against AD under nitrative stress.
(Less)
- author
- Hu, Ting ; Wu, Jinming LU ; Fu, Shitao ; Li, Hailing and Gao, Zhonghong
- organization
- publishing date
- 2025-05
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer's disease, Amyloid-β (Aβ), Kinetics, Neurodegenerative disease, Protein aggregation, Protein modifications, Tyrosine amination
- in
- International Journal of Biological Macromolecules
- volume
- 306
- article number
- 141700
- publisher
- Elsevier
- external identifiers
-
- scopus:85219415616
- pmid:40043970
- ISSN
- 0141-8130
- DOI
- 10.1016/j.ijbiomac.2025.141700
- language
- English
- LU publication?
- yes
- id
- 9b07396d-f73c-46fc-814f-f8a083243d68
- date added to LUP
- 2025-06-18 12:55:28
- date last changed
- 2025-07-16 15:55:28
@article{9b07396d-f73c-46fc-814f-f8a083243d68,
abstract = {{<p>The tyrosine residue in amyloid-β (Aβ) is susceptible to attack by various reactive nitrogen intermediates, leading to the formation of 3-nitrotyrosine (3-NT), a post-translational modification associated with the pathophysiology of Alzheimer's disease (AD). Although considered a “dead-end” product, emerging evidence suggests that 3-NT can be reduced to 3-aminotyrosine (3-AT) in vivo. This study aims to validate the amination of Aβ tyrosine under physiological conditions and systematically investigate its impact on the aggregation and neurotoxicity of Aβ42. Our investigations reveal that tyrosine amination mitigates the highly ordered β-structure content of Aβ42, thereby modulating its aggregation pathway, which is primarily dominated by the multi-step secondary nucleation. Aminotyrosine fibrils exhibit enhanced fragmentation, increasing fibril elongation rate, and insoluble aggregate production. Concurrently, tyrosine amination attenuates the neurotoxicity of Aβ42 by reducing intracellular reactive oxygen species (ROS) production and mitigating cell membrane disruption. Tyrosine amination substantially alters the aggregation and physiological properties of Aβ42. Nitration of Aβ42 and subsequent conversion to tyrosine-aminated Aβ42 may represent an intrinsic defensive response against AD under nitrative stress.</p>}},
author = {{Hu, Ting and Wu, Jinming and Fu, Shitao and Li, Hailing and Gao, Zhonghong}},
issn = {{0141-8130}},
keywords = {{Alzheimer's disease; Amyloid-β (Aβ); Kinetics; Neurodegenerative disease; Protein aggregation; Protein modifications; Tyrosine amination}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{International Journal of Biological Macromolecules}},
title = {{Impact of tyrosine amination on the aggregation and neurotoxicity of amyloid-β}},
url = {{http://dx.doi.org/10.1016/j.ijbiomac.2025.141700}},
doi = {{10.1016/j.ijbiomac.2025.141700}},
volume = {{306}},
year = {{2025}},
}