The nature of tyrosine-aminated amyloid-β

Author:

Gao Zhonghong1ORCID,Hu Ting1,Wu Jinming2,Fu Shitao1,Li Hailing1

Affiliation:

1. Huazhong University of Science and Technology

2. Lund University

Abstract

Abstract 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 nitration was considered a "dead-end" product, emerging evidence suggests that 3-NT can be reduced to aminotyrosine 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 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 its subsequent conversion to tyrosine-aminated Aβ42 may represent an intrinsic defensive response against AD under nitrative stress.

Publisher

Research Square Platform LLC

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