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Dysregulation of formaldehyde (FA) has been implicated in the development of Alzheimer's Disease (AD). Elevated FA levels in Alzheimer's patients and animal models are associated with impaired cognitive functions. However, the exact role of FA in AD remains unknown. We now identified that oxidative demethylation at serine8/26 of amyloid-beta protein (Aβ) induced FA generation and FA cross-linked with the lysine28 residue in the β-turn of monomer to form dimers, and then accelerated oligomerization and fibrillogenesis in vitro. However, Aβ42 mutation in serine8/26, lysine28 abolished self-aggregation. Furthermore, inhibited the activity of formaldehyde dehydrogenase (FDH), the enzyme for FA degradation, resulting in FA accumulation. In turn, excess of FA stimulated aggregation both in vitro and in vivo by increasing the formation of oligomers and fibrils. We found that degradation of FA by formaldehyde scavenger-NaHSO3 or coenzyme Q10 reduced aggregation and ameliorated the neurotoxicity, and improved the cognitive performance in APP/PS1 mice. Our study provides evidence that endogenous FA is essential for self-aggregation and scavenging FA could be an effective strategy for treating AD. © 2020. The Author(s).


Xuechao Fei, Yun Zhang, Yufei Mei, Xiangpei Yue, Wenjing Jiang, Li Ai, Yan Yu, Hongjun Luo, Hui Li, Wenhong Luo, Xu Yang, Jihui Lyv, Rongqiao He, Weihong Song, Zhiqian Tong. Degradation of FA reduces Aβ neurotoxicity and Alzheimer-related phenotypes. Molecular psychiatry. 2021 Oct;26(10):5578-5591

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PMID: 33328587

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