2. Academic Validation
  3. Degradation of FA reduces Aβ neurotoxicity and Alzheimer-related phenotypes

Degradation of FA reduces Aβ neurotoxicity and Alzheimer-related phenotypes

  • Mol Psychiatry. 2021 Oct;26(10):5578-5591. doi: 10.1038/s41380-020-00929-7.
Xuechao Fei # 1,  Yun Zhang # 2 3,  Yufei Mei # 1 4,  Xiangpei Yue # 1,  Wenjing Jiang 1 5,  Li Ai 1,  Yan Yu 6,  Hongjun Luo 7,  Hui Li 7,  Wenhong Luo 7,  Xu Yang 8,  Jihui Lyv 5,  Rongqiao He 1 9,  Weihong Song 10 11,  Zhiqian Tong 12
Affiliations

Affiliations

  • 1 Alzheimer's disease Center, Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, 100069, Beijing, China.
  • 2 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China.
  • 3 Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
  • 4 School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 5 Center for Cognitive Disorders, Beijing Geriatric Hospital, 100095, Beijing, China.
  • 6 Chinese institute of Rehabilitation Science, China Rehabilitation Research Center, Beijing Key Laboratory of Neural Injury and Rehabilitation, 100068, Beijing, China.
  • 7 Central Laboratory, Shantou University Medical College, Guangdong, 515041, China.
  • 8 Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, China.
  • 9 State Key Lab of Brain and Cognitive Science and Key Lab of Mental Health, IBP, UCAS, Beijing, China.
  • 10 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China. weihong@mail.ubc.ca.
  • 11 Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. weihong@mail.ubc.ca.
  • 12 Alzheimer's disease Center, Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, 100069, Beijing, China. tzqbeida@ccmu.edu.cn.
  • # Contributed equally.
PMID: 33328587 DOI: 10.1038/s41380-020-00929-7
Abstract

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 Aβ monomer to form Aβ dimers, and then accelerated Aβ oligomerization and fibrillogenesis in vitro. However, Aβ42 mutation in serine8/26, lysine28 abolished Aβ self-aggregation. Furthermore, Aβ inhibited the activity of formaldehyde dehydrogenase (FDH), the enzyme for FA degradation, resulting in FA accumulation. In turn, excess of FA stimulated Aβ aggregation both in vitro and in vivo by increasing the formation of Aβ oligomers and fibrils. We found that degradation of FA by formaldehyde scavenger-NaHSO3 or coenzyme Q10 reduced Aβ aggregation and ameliorated the neurotoxicity, and improved the cognitive performance in APP/PS1 mice. Our study provides evidence that endogenous FA is essential for Aβ self-aggregation and scavenging FA could be an effective strategy for treating AD.

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